Rheumatoid Arthritis Stem Cell Treatment

Rheumatoid Arthritis and Stem Cell Therapy

Stem Cell Treatment Rheumatoid ArthritisRheumatoid Arthritis and Stem Cell Therapy
Rheumatoid arthritis (RA), is a chronic system wide inflammatory disorder that may affect many tissues and organs however RA primarilly attacks the joints.

Stem Cell Treatmenst for Rheumatoid Arthritis is available. The Disease process often leads to the decay of articular cartilage and ankylosis of the joints. Rheumatoid Arthritis can also produce diffuse inflammation in the lungs, pericardium, pleura, and sclera, and also nodular lesions, most common in subcutaneous tissue.

Although the cause of Rheumatoid Arthritis is unknown, autoimmunity plays a pivotal role in both its chronic status and progression. RA is considered a systemic autoimmune disease.

 

 

STEM CELL RESEARCH

Stem Cell Treatment Rheumatoid Arthritis

Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications.
Yi T, Song SU.
2012 Feb;35(2):213-21. Epub 2012 Feb 28.

Source
Clinical Research Center, Inha Research Institute, Inha University School of Medicine, Incheon, 400-712, Korea.

Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that can be isolated from most adult tissues, including bone marrow, adipose, liver, amniotic fluid, lung, skeletal muscle and kidney. The term MSC is currently being used to represent both mesenchymal stem cells and multipotent mesenchymal stromal cells. Numerous reports on systemic administration of MSCs leading to functional improvements based on the paradigm of engraftment and differentiation have been published. However, it is not only difficult to demonstrate extensive engraftment of cells, but also no convincing clinical results have been generated from phase 3 trials as of yet and prolonged responses to therapy have been noted after identification of MSCs had discontinued. It is now clear that there is another mechanism by which MSCs exert their reparative benefits. Recently, MSCs have been shown to possess immunomodulatory properties. These include suppression of T cell proliferation, influencing dendritic cell maturation and function, suppression of B cell proliferation and terminal differentiation, and immune modulation of other immune cells such as NK cells and macrophages. In terms of the clinical applications of MSCs, they are being tested in four main areas: tissue regeneration for cartilage, bone, muscle, tendon and neuronal cells; as cell vehicles for gene therapy; enhancement of hematopoietic stem cell engraftment; and treatment of immune diseases such as graft-versus-host disease, rheumatoid arthritis, experimental autoimmune encephalomyelitis, sepsis, acute pancreatitis and multiple sclerosis. In this review, the mechanisms of immunomodulatory effects of MSCs and examples of animal and clinical uses of their immunomodulatory effects are described.
Haematopoietic stem cell gene therapy as a treatment for autoimmune diseases.

Mol Pharm. 2011 Jul 6;

Authors: Alderuccio F, Nasa Z, Chung J, Ko H, Chan J, Toh BH

A key function of the immune system is to protect us from foreign pathogens such as viruses, bacteria and parasites. However, it is also important in many other aspects of human health such as cancer surveillance, tissue transplantation, allergy and autoimmune disease. Autoimmunity can be defined as a chronic immune response that targets self-antigens leading to tissue pathology and clinical disease.

As a group of diseases that include type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, there are no effective cures and treatment is often based on long-term broad-spectrum immunosuppressive regimes.

While a number of strategies aimed at providing disease specific treatments are being explored, one avenue of study involves the use of haematopoietic stem cells to promote tolerance. In this manuscript, we will review the literature in this area but in particular examine the relatively new experimental field of gene therapy and haematopoietic stem cells transplantation as a molecular therapeutic to combat autoimmune disease.

PMID: 21732672 [PubMed - as supplied by publisher]

Mesenchymal stem cells: Re-establishing immunological tolerance in autoimmune rheumatic diseases.

Arthritis Rheum. 2011 Jun 6;

Authors: Macdonald GI, Augello A, De Bari C

Immunological tolerance is critical in preventing autoimmune disease and maintaining immune homeostasis. Increased understanding regarding cytokine networks led to the development of neutralizing antibodies against TNF alpha, IL-1 and IL-6 signalling in the treatment of rheumatoid arthritis (RA). However, there remains an unmet need given the significant number of patients not achieving remission nor responding to these drugs. Mesenchymal (stromal) stem cells (MSCs) are promising tools for the repair of damaged joint tissues such as cartilage, bone and tendons.

They also have potent anti-inflammatory and immunomodulatory properties both in vitro and in vivo [1]. Research into MSC therapy for Crohn's disease, type I diabetes, graft-versus-host disease (GvHD) and multiple sclerosis continues apace with phase II/III trials ongoing. There have been conflicting reports regarding their effects in the autoimmune rheumatic diseases, particularly in the collagen-induced arthritis mouse model of RA [2-8].

Conversely, promising results in patients with systemic lupus erythematosus (SLE) were recently reported [9] even in the face of conflicting results in murine models of SLE. In this article we will examine MSCs as a possible cellular therapy for RA, SLE and systemic sclerosis (SSc) and critically review possible reasons for conflicting results in the literature. We will also address whether MSC dysfunction could play a role in the aetiopathogenesis of these conditions.

Finally, we will examine the possible mechanisms of MSCs at a cellular level including the effects on regulatory T (Treg) cells and type 17 T helper (Th17) cell populations.

PMID: 21647863 [PubMed - as supplied by publisher]

Autologous hematopoietic stem cell transplantation in autoimmune diseases.

Expert Rev Hematol. 2009 Dec;2(6):699-715

Authors: Annaloro C, Onida F, Lambertenghi Deliliers G

The term 'autoimmune diseases' encompasses a spectrum of diseases whose clinical manifestations and, possibly, biological features vary widely. The results of conventional treatment are considered unsatisfactory in aggressive forms, with subsets of patients having short life expectancies.

Relying on wide experimental evidence and more feeble clinical data, some research groups have used autologous hematopoietic stem cell transplantation (HSCT) in the most disabling autoimmune diseases with the aim of resetting the patient's immune system.

Immunoablative conditioning regimens are preferred over their myeloablative counterparts, and some form of in vivo and/or ex vivo T-cell depletion is generally adopted.

Despite 15 years' experience, published controlled clinical trials are still lacking, with the evidence so far available coming from pilot studies and registry surveys.

In multiple sclerosis, clinical improvement, or at least lasting disease stabilization, can be achieved in the majority of the patients; nevertheless, the worst results are observed in patients with progressive disease, where no benefit can be expected from conventional therapy.

Stem Cell Therapy Rheumatoid Arthritis

Stem Cell Therapy for Rheumatic Disease

Concerning rheumatologic diseases, wide experience has been acquired in systemic sclerosis, with long-term improvements in cutaneous disease being frequently reported, although visceral involvement remains unchanged at best. Autografting has proved to be barely effective in rheumatoid arthritis and quite toxic in juvenile idiopathic arthritis, whereas it leads to clinical remission and the reversal of visceral impairment in the majority of patients with systemic lupus erythematosus.

A promising indication is Crohn's disease, in which long-term endoscopic remission is frequently observed. Growing experience with autologous HCST in autoimmune diseases has progressively reduced concerns about transplant-related mortality and secondary myelodysplasia/leukemia.

Therefore, a sustained complete remission seems to be within the reach of autografting in some autoimmune diseases; in others, the indications, risks and benefits of autografting need to be better defined. Consequently, the search for new drugs should also be encouraged.

Related Articles MSC Therapeutics in Chronic Inflammation. Curr Stem Cell Rep. 2016 Jun;2(2):168-173 Authors: Sargent A, Miller RH Abstract The utilization of mesenchymal stem cells (also known as mesenchymal stromal cells, or MSCs) as a cell-based therapy for diseases that have ongoing inflammatory damage has become increasingly available. Our understanding of the cell biology of MSCs is still incomplete. However, as a result of increasing numbers of pre-clinical and clinical studies, general themes are emerging. The capacity of MSCs to reduce disease burden is largely associated with their ability to modulate the activity of the host immune responses rather than to contribute directly to tissue regeneration. As a result, they have significant potential in the treatment of chronic inflammatory disease regardless of the affected tissue. For example, MSC based therapies have been developed in the context of diseases as diverse as rheumatoid arthritis and multiple sclerosis. Here we discuss some of the principles that link these conditions, and the aspects of MSC biology that contribute to their use as a therapy for chronic inflammatory conditions. PMID: 28133600 [PubMed]
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Related Articles Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence. Mol Cell Endocrinol. 2017 Nov 05;455:4-12 Authors: Choi IY, Lee C, Longo VD Abstract Complex and coordinated signals are necessary to initiate and sustain the activation, proliferation, and differentiation of lymphocytes. These signals, which are known to determine T-cell fate and function, also depend on the metabolic state of the organism. Recent studies indicate that both the type and levels of nutrients can influence the generation, survival and function of lymphocytes and therefore can affect several autoimmune diseases. Here, we review the dysregulation of lymphocytes during autoimmunity and aging, the mechanisms associated with loss of immune function, and how fasting mimicking diets and other dietary interventions affect autoimmunity and immunosenescence. PMID: 28137612 [PubMed - indexed for MEDLINE]
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Related Articles Immunoselected STRO-3+ mesenchymal precursor cells reduce inflammation and improve clinical outcomes in a large animal model of monoarthritis. Stem Cell Res Ther. 2017 02 07;8(1):22 Authors: Abdalmula A, Dooley LM, Kaufman C, Washington EA, House JV, Blacklaws BA, Ghosh P, Itescu S, Bailey SR, Kimpton WG Abstract BACKGROUND: The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis. METHODS: Monoarthritis was established in 16 adult merino sheep by administration of bovine type II collagen into the left hock joint following initial sensitization to this antigen. After 24 h, sheep were administered either 150 million allogeneic ovine MPCs (n = 8) or saline (n = 8) intravenously (IV). Lameness, joint swelling and pain were monitored and blood samples for leukocytes and cytokine levels were collected at intervals following arthritis induction. Animals were necropsied 14 days after arthritis induction and gross and histopathological evaluations were undertaken on tissues from the arthritic (left) and contralateral (right) joints. RESULTS: MPC-treated sheep demonstrated significantly reduced clinical signs of lameness, joint pain and swelling compared with saline controls. They also showed decreased cartilage erosions, synovial stromal cell activation and angiogenesis. This was accompanied by decreased infiltration of the synovial tissues by CD4+ lymphocytes and CD14+ monocytes/macrophages. Over the 3 days following joint arthropathy induction, the numbers of neutrophils circulating in the blood and plasma concentrations of activin A were significantly reduced in animals administered MPCs. CONCLUSIONS: The results of this study have demonstrated the capacity of IV-administered MPCs to mitigate the clinical signs and some of the inflammatory mediators responsible for joint tissue destruction in a large animal model of monoarthritis. PMID: 28173831 [PubMed - indexed for MEDLINE]
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Related Articles Identification of Potential Plasma microRNA Stratification Biomarkers for Response to Allogeneic Adipose-Derived Mesenchymal Stem Cells in Rheumatoid Arthritis. Stem Cells Transl Med. 2017 Apr;6(4):1202-1206 Authors: Mallinson DJ, Dunbar DR, Ridha S, Sutton ER, De la Rosa O, Dalemans W, Lombardo E Abstract The ability to identify and stratify patients that will respond to specific therapies has been transformational in a number of disease areas, particularly oncology. It is anticipated that this will also be the case for cell-based therapies, particularly in complex and heterogeneous diseases such as rheumatoid arthritis (RA). Recently, clinical results with expanded allogenic adipose-derived mesenchymal stem cells (eASCs) have indicated clinical efficacy in highly refractory RA patients. In this study, we set out to determine if circulating microRNAs (miRNAs) could be identified as potential biomarkers associated with response to eASCs in these RA patients. The miRNA expression profiles of pre-treatment plasma samples from responder and nonresponder patients were determined using microarrays. Ten miRNAs were identified that were differentially expressed in the responder group as compared to the nonresponder group. To confirm the differential expression of these 10 miRNA biomarkers, they were further assayed by quantitative reverse-transcriptase polymerase chain reaction (QRT-PCR). From this analysis, three miRNAs, miR-26b-5p, miR-487b-3p and miR-495-3p, were confirmed as being statistically significantly upregulated in the responder group as compared with the nonresponder group. Receiver operating characteristic analysis confirmed their diagnostic potential. These miRNAs could represent novel candidate stratification biomarkers associated with RA patient response to eASCs and are worthy of further clinical validation. Stem Cells Translational Medicine 2017;6:1202-1206. PMID: 28186687 [PubMed - in process]
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Related Articles Multipotent Stem Cell and Current Application. Acta Med Iran. 2017 Jan;55(1):6-23 Authors: Sobhani A, Khanlarkhani N, Baazm M, Mohammadzadeh F, Najafi A, Mehdinejadiani S, Sargolzaei Aval F Abstract Stem cells are self-renewing and undifferentiated cell types that can be differentiate into functional cells. Stem cells can be classified into two main types based on their source of origin: Embryonic and Adult stem cells. Stem cells also classified based on the range of differentiation potentials into Totipotent, Pluripotent, Multipotent, and Unipotent. Multipotent stem cells have the ability to differentiate into all cell types within one particular lineage. There are plentiful advantages and usages for multipotent stem cells. Multipotent Stem cells act as a significant key in procedure of development, tissue repair, and protection. Multipotent Stem cells have been applying in treatment of different disorders such as spinal cord injury, bone fracture, autoimmune diseases, rheumatoid arthritis, hematopoietic defects, and fertility preservation. PMID: 28188938 [PubMed - indexed for MEDLINE]
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Related Articles Anti-arthritic property of crude extracts of Piptadeniastrum africanum (Mimosaceae) in complete Freund's adjuvant-induced arthritis in rats. BMC Complement Altern Med. 2017 Feb 15;17(1):111 Authors: Mbiantcha M, Almas J, Shabana SU, Nida D, Aisha F Abstract BACKGROUND: Rheumatoid arthritis, disease of unknown causes is a rheumatic and autoimmune pathology, recognised for its increasing frequency and its adverse consequences. It is a disease that occurs in most cases between 50 and 60 years and women are more affected than men. This study aimed at evaluating immunomodulatory and anti-arthritis capacity of aqueous and methanol extracts of stem bark of Piptadeniastrum africanum (Mimosaceae). METHODS: ROS production from phagocytes, proliferation of T-cells, TNF-α and IL-1β production and cytotoxicity were performed by using chemiluminescence technique, liquid scintillation counter, ELISA and MTT assay, respectively. Anti-arthritic activity was evaluated using a model of adjuvant induced arthritis. RESULTS: Methanol and aqueous extracts of Piptadeniastrum africanum significantly (P < 0.001) inhibited extracellular and intracellular ROS production. These extracts also possess significant (P < 0.001) inhibitory activity on T-cell proliferation other than reduced TNF-α and IL-1β production. Piptadeniastrum africanum also significantly exhibited antiarthritic activity in complete Freund's adjuvant induced arthritis in rat associated with a significant anti-inflammatory and anti-hyperalgesia activity. CONCLUSIONS: Immunomodulatory, anti-inflammatory, antihyperalgesia and anti-arthritis potential revealed in this study approve that, Piptadeniastrum africanum is a plant rich in compounds with anti-arthritic properties. PMID: 28202019 [PubMed - indexed for MEDLINE]
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Related Articles Burden of musculoskeletal disorders in the Eastern Mediterranean Region, 1990-2013: findings from the Global Burden of Disease Study 2013. Ann Rheum Dis. 2017 Aug;76(8):1365-1373 Authors: Moradi-Lakeh M, Forouzanfar MH, Vollset SE, El Bcheraoui C, Daoud F, Afshin A, Charara R, Khalil I, Higashi H, Abd El Razek MM, Kiadaliri AA, Alam K, Akseer N, Al-Hamad N, Ali R, AlMazroa MA, Alomari MA, Al-Rabeeah AA, Alsharif U, Altirkawi KA, Atique S, Badawi A, Barrero LH, Basulaiman M, Bazargan-Hejazi S, Bedi N, Bensenor IM, Buchbinder R, Danawi H, Dharmaratne SD, Zannad F, Farvid MS, Fereshtehnejad SM, Farzadfar F, Fischer F, Gupta R, Hamadeh RR, Hamidi S, Horino M, Hoy DG, Hsairi M, Husseini A, Javanbakht M, Jonas JB, Kasaeian A, Khan EA, Khubchandani J, Knudsen AK, Kopec JA, Lunevicius R, Abd El Razek HM, Majeed A, Malekzadeh R, Mate K, Mehari A, Meltzer M, Memish ZA, Mirarefin M, Mohammed S, Naheed A, Obermeyer CM, Oh IH, Park EK, Peprah EK, Pourmalek F, Qorbani M, Rafay A, Rahimi-Movaghar V, Shiri R, Rahman SU, Rai RK, Rana SM, Sepanlou SG, Shaikh MA, Shiue I, Sibai AM, Silva DAS, Singh JA, Skogen JC, Terkawi AS, Ukwaja KN, Westerman R, Yonemoto N, Yoon SJ, Younis MZ, Zaidi Z, Zaki MES, Lim SS, Wang H, Vos T, Naghavi M, Lopez AD, Murray CJL, Mokdad AH Abstract OBJECTIVES: We used findings from the Global Burden of Disease Study 2013 to report the burden of musculoskeletal disorders in the Eastern Mediterranean Region (EMR). METHODS: The burden of musculoskeletal disorders was calculated for the EMR's 22 countries between 1990 and 2013. A systematic analysis was performed on mortality and morbidity data to estimate prevalence, death, years of live lost, years lived with disability and disability-adjusted life years (DALYs). RESULTS: For musculoskeletal disorders, the crude DALYs rate per 100 000 increased from 1297.1 (95% uncertainty interval (UI) 924.3-1703.4) in 1990 to 1606.0 (95% UI 1141.2-2130.4) in 2013. During 1990-2013, the total DALYs of musculoskeletal disorders increased by 105.2% in the EMR compared with a 58.0% increase in the rest of the world. The burden of musculoskeletal disorders as a proportion of total DALYs increased from 2.4% (95% UI 1.7-3.0) in 1990 to 4.7% (95% UI 3.6-5.8) in 2013. The range of point prevalence (per 1000) among the EMR countries was 28.2-136.0 for low back pain, 27.3-49.7 for neck pain, 9.7-37.3 for osteoarthritis (OA), 0.6-2.2 for rheumatoid arthritis and 0.1-0.8 for gout. Low back pain and neck pain had the highest burden in EMR countries. CONCLUSIONS: This study shows a high burden of musculoskeletal disorders, with a faster increase in EMR compared with the rest of the world. The reasons for this faster increase need to be explored. Our findings call for incorporating prevention and control programmes that should include improving health data, addressing risk factors, providing evidence-based care and community programmes to increase awareness. PMID: 28209629 [PubMed - indexed for MEDLINE]
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Related Articles Compact Bone-Derived Multipotent Mesenchymal Stromal Cells (MSCs) for the Treatment of Sjogren's-like Disease in NOD Mice. Methods Mol Biol. 2017;1553:25-39 Authors: Elghanam GA, Liu Y, Khalili S, Fang D, Tran SD Abstract Compact bone (cortical or dense bone) is among the organs that contain multipotent mesenchymal stromal cells (MSCs). Unlike bone marrow plugs where MSCs were initially isolated, compact bone has minimal (amount of) hematopoietic cells and thus facilitates the MSCs isolation process. In vitro, MSCs from compact bone show multipotency and differentiation into mesenchymal tissues such as bone, adipose, and cartilage, under certain conditions. MSCs therapy has been promising in preclinical and clinical studies against autoimmune diseases. Not only can MSCs replace the lost tissue through their regenerative properties, but they can also control the autoimmune attacks by immunoregulatory cytokines. This protocol describes the use of compact bone-derived MSCs to preserve salivary function (saliva flow/output) in the NOD (nonobese diabetic) mouse model affected with Sjogren's-like disease. PMID: 28229405 [PubMed - indexed for MEDLINE]
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Related Articles Synergistic suppression of autoimmune arthritis through concurrent treatment with tolerogenic DC and MSC. Sci Rep. 2017 02 23;7:43188 Authors: Li R, Zhang Y, Zheng X, Peng S, Yuan K, Zhang X, Min W Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive immune-mediated joint deterioration. Current treatments are not antigen specific and are associated with various adverse. We have previously demonstrated that tolerogenic dendritic cells (Tol-DC) are potent antigen-specific immune regulators, which hold great promise in immunotherapy of autoimmune diseases. In this study, we aimed to develop new immunotherapy by combining Tol-DC and mesenchymal stem cells (MSC). We demonstrated that RelB gene silencing resulted in generation of Tol-DC that suppressed T cell responses and selectively promoted Treg generation. The combination of MSC synergized the tolerogenic capacity of Tol-DC in inhibition of T cell responses. In murine collagen-induced arthritis (CIA) model, we demonstrated that progression of arthritis was inhibited with administration of RelB gene-silenced Tol-DC or MSC. This therapeutic effect was remarkably enhanced with concurrent treatment of combination Tol-DC and MSC as demonstrated by improved clinical symptoms, decreased clinical scores and attenuated joint damage. These therapeutic effects were associated with suppression of CII-specific T cell responses, polarization of Th and inhibition of proinflammatory cytokines, and reduced cartilage degeneration. This study for the first time demonstrates a new approach to treat autoimmune inflammatory joint disease with concurrent treatment of RelB gene-silenced Tol-DC and MSC. PMID: 28230210 [PubMed - indexed for MEDLINE]
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Related Articles Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review. Cell Immunol. 2017 05;315:1-10 Authors: Shirjang S, Mansoori B, Solali S, Hagh MF, Shamsasenjan K Abstract Understanding the role of toll-like receptors (TLRs) in the immunomodulation potential, differentiation, migration, and survival of mesenchymal stem cells (MSCs) is absolutely vital to fully exploiting their MSC-based therapeutic potential. Furthermore, through recognition of exogenous or endogenous ligands produced upon injury, TLRs have been linked to allograft rejection and maintenance of chronic inflammatory diseases, including Crohn's disease, rheumatoid arthritis. Characterizing the effect of TLRs in biological control of MSCs fate and function could improve our knowledge about the MSC-based cell therapy and immunotherapy. In this paper, we outline the impacts of TLR activation and mechanisms on MSCs immunomodulatory functions, differentiation, migration, and survivability. Moreover, we indicate that the expression patterns of TLRs in MSCs from different sources. PMID: 28284487 [PubMed - indexed for MEDLINE]
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Related Articles Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis. Biomed Res Int. 2017;2017:2690402 Authors: Perpétuo IP, Caetano-Lopes J, Rodrigues AM, Campanilho-Marques R, Ponte C, Canhão H, Ainola M, Fonseca JE Abstract Objective. Tumor necrosis factor (TNF) increases circulating osteoclast (OC) precursors numbers by promoting their proliferation and differentiation. The aim of this study was to assess the effect of TNF inhibitors (TNFi) on the differentiation and activity of OC in rheumatoid arthritis (RA) patients. Methods. Seventeen RA patients treated with TNFi were analyzed at baseline and after a minimum follow-up period of 6 months. Blood samples were collected to assess receptor activator of nuclear factor kappa-B ligand (RANKL) surface expression on circulating leukocytes and frequency and phenotype of monocyte subpopulations. Quantification of serum levels of bone turnover markers, in vitro OC differentiation assays, and qRT-PCR for OC specific genes was performed. Results. After TNFi therapy, patients had reduced RANKL surface expression in B-lymphocytes and the frequency of circulating classical CD14brightCD16- monocytes was decreased. Serum levels of sRANKL, sRANKL/OPG ratio, and CTX-I were reduced in RA patients after TNFi treatment. Moreover, after exposure to TNFi, osteoclast differentiation and activity were decreased, as well as the expression of TRAF6 and cathepsin K. Conclusion. We propose that TNFi arrests bone loss and erosion, through two pathways: direct reduction of osteoclast precursor numbers and inhibition of intracellular signaling pathways acting through TRAF6. PMID: 28286757 [PubMed - indexed for MEDLINE]
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Related Articles [Effect of allogenic mesenchymal stem cells transplantation on the expression of interleukin-22 and matrix metalloproteinase-3 in rats with collagen induced arthritis]. Zhonghua Yi Xue Za Zhi. 2017 Mar 07;97(9):698-702 Authors: Liu GY, Bian S, Li F, Li XF, Fan K, An HZ, Jia XX Abstract Objective: To study the effect of allogeneic bone marrow mesenchymal stem cells transplantation on the expression of interleukin -22 (IL-22), matrix metalloproteinase -3 (MMP-3) in serum and synovial of rats with collagen induced arthritis. Methods: Type Ⅱ collagen were injected twice to establish the collagen induced arthritis (CIA) rat model. Forty-eight rats were randomly divided into 3 groups: control group, CIA control group, CIA experiment group. Rat bone marrow mesenchymal stem cells were cultured by bone marrow method combined with adherent culture method. After identify, the remaining cells were injected in the CIA experimental group. Enzyme linked immunosorbent assay (ELISA) and immunohistochemistry were used to detect the expression of IL-22 and MMP-3 in serum and anklebone joint's synovium of rats, respectively. Synovial cells were isolated and cultured, and were treated with different concentrations of IL-22. MMP-3 protein and mRNA were detected before and after stimulation by Western blot and real-time quantitative polymerase chain reaction (RT-qPCR). Results: After MSC transplantation, arthritis index, X-ray, HE staining of CIA rat showed that joint damage significantly reduced compared with the control group. The ELISA results showed that the expression of MMP-3 and IL-22 in CIA control group was higher than those in the control group (125.79±9.12 vs 102.00±7.63 ng/ml, P<0.05), (292.35±31.23 vs 257.27±13.99 ng/ml, P<0.05) and CIA experiment group (125.79±9.12 vs 97.94±9.50 ng/ml, P<0.05), (292.35±31.23 vs 262.16±22.02 ng/ml, P<0.05) with statistically significant difference (P<0.05). There was no significant difference between the control group and CIA experimental group. Immunohistochemical showed similar results with ELISA. Western blotting and RT-qPCR showed that MMP-3 protein and mRNA expression was increased after IL-22 stimulation in a dose-dependent manner. Conclusion: IL-22 and MMP-3 play an important role in the pathogenesis of rheumatoid arthritis. IL-22 could regulate the expression of MMP-3, and bone marrow mesenchymal stem cells could reduce the expression of MMP-3 in the treatment of rheumatoid arthritis by reducing the expression of IL-22. PMID: 28297833 [PubMed - indexed for MEDLINE]
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Related Articles Mesenchymal stromal cells and autoimmunity. Int Immunol. 2017 Feb 01;29(2):49-58 Authors: Pistoia V, Raffaghello L Abstract Mesenchymal stromal cells (MSCs) are committed progenitors of mesodermal origin that are found virtually in every organ and exhibit multilineage differentiation into osteocytes, adipocytes and chondrocytes. MSCs also mediate a wide spectrum of immunoregulatory activities that usually dampen innate and adaptive immune responses. These features have attracted interest in the perspective of developing novel cell therapies for autoimmune disease. However, depending on the microenvironmental conditions, MSCs may show a plastic behavior and switch to an immunostimulatory phenotype. After thorough characterization of the effects of MSCs on the immune system, MSC cell therapy has been tested in animal models of autoimmunity using different cell sources, protocols of in vitro expansion and routes and schedules of administration. The pre-clinical results have been encouraging in some models [e.g. Crohn's disease (CD), multiple sclerosis] and heterogeneous in others (e.g. graft-versus-host disease, systemic lupus erythematosus, rheumatoid arthritis). Clinical trials have been carried out and many are ongoing. As discussed, the results obtained are too preliminary to draw any conclusion, with the only exception of topical administration of MSCs in CD that has proven efficacious. The mechanism of action of infused MSCs is still under investigation, but the apparent paradox of a therapeutic effect achieved in spite of the very low number of cells reaching the target organ has been solved by the finding that MSC-derived extracellular vesicles (EVs) closely mimic the therapeutic activity of MSCs in pre-clinical models. These issues are critically discussed in view of the potential clinical use of MSC-derived EVs. PMID: 28338763 [PubMed - indexed for MEDLINE]
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Related Articles Human adipose tissue-derived mesenchymal stem cells in rheumatoid arthritis: Regulatory effects on peripheral blood mononuclear cells activation. Int Immunopharmacol. 2017 Jun;47:59-69 Authors: Baharlou R, Ahmadi-Vasmehjani A, Faraji F, Atashzar MR, Khoubyari M, Ahi S, Erfanian S, Navabi SS Abstract BACKGROUND AND OBJECTIVES: Mesenchymal stem cells (MSCs) are multipotent adult stem cells with immunomodulatory properties. The mechanisms by which MSCs inhibit the proliferation of pro-inflammatory T cells have not been fully elucidated yet. It is assumed that pro-inflammatory T-cells play an important role in the development of autoimmune diseases. We investigated the potential therapeutic effects of human adipose tissue derived (Ad)-MSCs on the peripheral blood mononuclear cells (PBMCs) of rheumatoid arthritis (RA) patients and healthy individuals, with a particular focus on Th17-associated cytokines. MATERIALS AND METHODS: PBMCs from RA patients and healthy donors were co-cultured with Ad-MSCs and HeLa with or without Phytohemagglutinin (PHA). Finally, IL-6, IL-17, IL-21, IL-23 and TGF-β levels were determined by ELISA and quantitative real-time RT-PCR on co-culture supernatants and PBMCs, respectively. RESULTS: In co-culture interaction, Ad-MSCs inhibited IL-17 secretion by PBMCs compared to unstimulated PBMCs cultured alone. In addition, IL-21 expressions in PBMCs of the patient group, and IL-17 and IL-21 in healthy group were inhibited by Ad-MSCs compared to PBMCs cultured alone. TGF-β expression in healthy individuals remarkably increased in both MSC-treated groups with and without PHA in comparison to PHA-stimulated and -unstimulated PBMCs. CONCLUSIONS: This study demonstrates that human Ad-MSCs act as key regulators of immune tolerance by inhibiting the inflammation. Therefore, they can be attractive candidates for immunomodulatory cell-based therapy in RA. PMID: 28364628 [PubMed - indexed for MEDLINE]
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Related Articles Adverse drug reactions after intravenous rituximab infusion are more common in hematologic malignancies than in autoimmune disorders and can be predicted by the combination of few clinical and laboratory parameters: results from a retrospective, multicenter study of 374 patients. Leuk Lymphoma. 2017 11;58(11):2633-2641 Authors: D'Arena G, Simeon V, Laurenti L, Cimminiello M, Innocenti I, Gilio M, Padula A, Vigliotti ML, De Lorenzo S, Loseto G, Passarelli A, Di Minno MND, Tucci M, De Feo V, D'Auria F, Silvestris F, Di Minno G, Musto P Abstract Rituximab is an effective treatment for CD20 + B-cell malignancies and autoimmune disorders. However, adverse drug reactions (ADRs) may occur after rituximab infusion, causing, in rare cases, its discontinuation. In this multicenter, retrospective study, among 374 patients treated with rituximab i.v., 23.5% experienced ADRs. Mean follow-up was 20.6 months (range 8-135). Overall, ADRs were significantly more frequent in non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemias (25-35.9%), than in autoimmune diseases (9.4-17.5%) (p < .0001). Grade 3-4 toxicity was observed in eight patients (2.1%), and in four of them (1% of all patients) definitive drug discontinuation was necessary. Interestingly, three groups of patients with different risk of developing ADR were identified, according to a predictive heat-map developed combining four parameters (splenomegaly, history of allergy, hemoglobin levels and gender) selected by multivariate analysis. This model may be useful in identifying patients at higher risk of ADRs, needing appropriate preventing therapies. PMID: 28367662 [PubMed - indexed for MEDLINE]
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Related Articles Mechanobiology of mesenchymal stem cells: Which interest for cell-based treatment? Biomed Mater Eng. 2017;28(s1):S47-S56 Authors: Huselstein C, Rahouadj R, de Isla N, Bensoussan D, Stoltz JF, Li YP Abstract Thanks to their immune properties, the mesenchymal stem cells (MSC) are a promising source for cell therapy. Current clinical trials show that MSC administrated to patients can treat different diseases (graft-versus-host disease (GVHD), liver cirrhosis, systemic lupus, erythematosus, rheumatoid arthritis, type I diabetes…). In this case, the most common mode of cell administration is the intravenous injection, and the hemodynamic environment of cells induced by blood circulation could interfere on their behavior during the migration and homing towards the injured site. After a brief review of the mechanobiology concept, this paper will help in understanding how the mechanical environment could interact with MSC behavior once they are injected to patient in cell-based treatment. PMID: 28372277 [PubMed - indexed for MEDLINE]
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Related Articles Evaluation of antigen-induced synovitis in a porcine model: Immunological, arthroscopic and kinetic studies. BMC Vet Res. 2017 Apr 07;13(1):93 Authors: Vela FJ, Sánchez-Margallo FM, Blázquez R, Álvarez V, Tarazona R, Mangas-Ballester MT, Cristo A, Casado JG Abstract BACKGROUND: Synovitis is an inflammation-related disease linked to rheumatoid arthritis, osteoarthritis, infections and trauma. This inflammation is accompanied by immune cells infiltration which initiates an inflammatory response causing pain, discomfort and affecting the normal joint function. The treatment of synovitis is based on the administration of anti-inflammatory drugs or biological agents such as platelet rich plasma and mesenchymal stem cells. However, the evaluation and validation of more effective therapies of synovitis requires the establishment of clinically relevant animal models. RESULTS: In this study, Large White pigs were pre-immunized to evaluate an antigen-induced synovitis. The immune monitoring of synovial fluids in this model allowed us the identification of IL-12p40 and T cell subsets as immune biomarkers. Moreover, the evolution of synovitis was performed by arthroscopic procedures and kinetic analysis. In summary, this paper describes an animal model of antigen-induced synovitis to be used in the evaluation of anti-inflammatory therapies. CONCLUSIONS: The novelty of this paper lies in the development of a clinically relevant model of synovitis which permits the simultaneous evaluation of synovitis from an immunological, surgical and kinetic point of view. PMID: 28388908 [PubMed - indexed for MEDLINE]
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Related Articles Endoscopic Manifestations and Clinical Characteristics of Cytomegalovirus Infection in the Upper Gastrointestinal Tract. Acta Med Okayama. 2017 Apr;71(2):97-104 Authors: Iwamuro M, Kondo E, Tanaka T, Hagiya H, Kawano S, Kawahara Y, Otsuka F, Okada H Abstract We retrospectively analyzed the cases of 14 patients (9 women, 5 men, mean age: 51.6 years) with cytomegalovirus (CMV) involvement in the esophagus, stomach, and/or duodenum diagnosed at a single center, to determine their endoscopic features and clinical backgrounds. Thirteen patients (92.9%) had hematologic disease; the other had rheumatoid arthritis. Of the former, 12 patients underwent allogeneic hematopoietic stem cell transplantation, and 9 of these patients had graft-versus-host disease (GVHD) before undergoing esophagogastroduodenoscopy (EGD). All 14 patients had been taking one or more immunosuppressive agents including cyclosporine (n=10), corticosteroids (n=9), mycophenolic acid (n=6), tacrolimus (n=3), and methotrexate (n=1). Tests for CMV antigenemia were positive in 11 patients (78.6%). EGD examinations revealed esophageal (n=3), gastric (n=9), and duodenal involvement (n=6). Macroscopically, esophageal lesions by CMV infection presented as redness (n=1), erosions (n=1), and ulcers (n=1). Gastric lesions manifested as redness (n=7), erosions (n=3), exfoliated mucosa (n=2), and verrucous erosions (n=1). Mucosal appearances in the duodenum varied: redness (n=2), ulcers (n=2), multiple erosions (n=2), single erosion (n=1), edema (n=1). CMV was detected even in the intact duodenal mucosa (n=1). In conclusion, physicians must recall the relevance of CMV infection when any mucosal alterations exist in the upper gastrointestinal tract of immunosuppressed patients. PMID: 28420890 [PubMed - indexed for MEDLINE]
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Related Articles Influence of sinomenine upon mesenchymal stem cells in osteoclastogenesis. Biomed Pharmacother. 2017 Jun;90:835-841 Authors: Zhou B, Lu X, Tang Z, Liu D, Zhou Y, Zeng P, Xiong H Abstract With the advent of aging, the morbidity rates of such diseases as osteoarthritis, rheumatoid arthritis, and osteoporosis has witnessed a significant increase. As a common rattan drug, sinomenine (SIN) has been widely applied for the treatment of various arthritic diseases in traditional Chinese medicine (TCM) clinics. Given that SIN has been reported to inhibit the expression of Prostaglandin E2 (PGE2) in several types of cells, in this study, the influence of SIN treatment on PGE2 expression in mesenchymal stem cells (MSCs), thereby changing the osteoprotegerin (OPG) receptor/activator for the nuclear factor-κ B ligand (RANKL) ratio, was investigated. Our results showed that, when compared with the untreated cells, treatment with 0.25mM SIN can down-regulate the mRNA and protein expression levels of the Prostaglandin E synthase 3 (PTGES3) or PGE2 and RANKL, while the OPG was up-regulated. After being cultured with SIN treated MSC-conditioned medium (stMSC-CM), the amount of TRAP-positive multinucleated osteoclasts differentiated from RAW264.7 cells was reduced. Also, the expression levels of specific markers for active osteoclasts were decreased when incubated with stMSC-CM. Moreover, these changes were able to be recovered when the exogenous RANKL was added to the MSC-CM culture. This indicates that the increased OPG/RANKL ratio can reduce the osteoclastogenesis of RAW264.7 cells. Our results demonstrated that SIN has an inhibitory effect on osteoclast differentiation through mechanisms involving the inhibition of the PGE2-induced OPG/RANKL ratio. SIN can also serve as a proinflammatory mediator to regulate the MSC immunosuppressive effects. Our findings suggest that SIN can be useful for the treatment of bone diseases associated with over-activity of osteoclasts. PMID: 28437887 [PubMed - indexed for MEDLINE]
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Related Articles Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles. Int J Mol Sci. 2017 Apr 22;18(4): Authors: Cosenza S, Ruiz M, Maumus M, Jorgensen C, Noël D Abstract Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted by all cell types and their function reproduces that of the parental cell. They are involved in many biological processes that regulate tissue homeostasis and physiopathology of diseases. In rheumatic diseases, namely osteoarthritis (OA) and rheumatoid arthritis (RA), EVs have been isolated from synovial fluid and shown to play pathogenic roles contributing to progression of both diseases. By contrast, EVs may have therapeutic effect via the delivery of molecules that may stop disease evolution. In particular, EVs derived from mesenchymal stem cells (MSCs) reproduce the main functions of the parental cells and therefore represent the ideal type of EVs for modulating the course of either disease. The aim of this review is to discuss the role of EVs in OA and RA focusing on their potential pathogenic effect and possible therapeutic options. Special attention is given to MSCs and MSC-derived EVs for modulating OA and RA progression with the perspective of developing innovative therapeutic strategies. PMID: 28441721 [PubMed - indexed for MEDLINE]
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Related Articles Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs. Stem Cell Reports. 2017 05 09;8(5):1202-1213 Authors: Brunger JM, Zutshi A, Willard VP, Gersbach CA, Guilak F Abstract Chronic inflammatory diseases such as arthritis are characterized by dysregulated responses to pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α). Pharmacologic anti-cytokine therapies are often effective at diminishing this inflammatory response but have significant side effects and are used at high, constant doses that do not reflect the dynamic nature of disease activity. Using the CRISPR/Cas9 genome-engineering system, we created stem cells that antagonize IL-1- or TNF-α-mediated inflammation in an autoregulated, feedback-controlled manner. Our results show that genome engineering can be used successfully to rewire endogenous cell circuits to allow for prescribed input/output relationships between inflammatory mediators and their antagonists, providing a foundation for cell-based drug delivery or cell-based vaccines via a rapidly responsive, autoregulated system. The customization of intrinsic cellular signaling pathways in stem cells, as demonstrated here, opens innovative possibilities for safer and more effective therapeutic approaches for a wide variety of diseases. PMID: 28457885 [PubMed - indexed for MEDLINE]
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Related Articles Intralymphatic Administration of Adipose Mesenchymal Stem Cells Reduces the Severity of Collagen-Induced Experimental Arthritis. Front Immunol. 2017;8:462 Authors: Mancheño-Corvo P, Lopez-Santalla M, Menta R, DelaRosa O, Mulero F, Del Rio B, Ramirez C, Büscher D, Bueren JA, Lopez-Belmonte J, Dalemans W, Garin MI, Lombardo E Abstract Mesenchymal stem cells (MSCs) are multipotent stromal cells with immunomodulatory properties. They have emerged as a very promising treatment for autoimmunity and inflammatory diseases such as rheumatoid arthritis. Previous studies have demonstrated that MSCs, administered systemically, migrate to lymphoid tissues associated with the inflammatory site where functional MSC-induced immune cells with a regulatory phenotype were increased mediating the immunomodulatory effects of MSCs. These results suggest that homing of MSCs to the lymphatic system plays an important role in the mechanism of action of MSCs in vivo. Thus, we hypothesized that direct intralymphatic (IL) (also referred as intranodal) administration of MSCs could be an alternative and effective route of administration for MSC-based therapy. Here, we report the feasibility and efficacy of the IL administration of human expanded adipose mesenchymal stem cells (eASCs) in a mouse model of collagen-induced arthritis (CIA). IL administration of eASCs attenuated the severity and progression of arthritis, reduced bone destruction and increased the levels of regulatory T cells (CD25+Foxp3+CD4+ cells) and Tr1 cells (IL10+CD4+), in spleen and draining lymph nodes. Taken together, these results indicate that IL administration of eASCs is very effective in modulating established CIA and may represent an alternative treatment modality for cell therapy with eASCs. PMID: 28484460 [PubMed]
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Related Articles Functional Analysis of Dendritic Cells Generated from T-iPSCs from CD4+ T Cell Clones of Sjögren's Syndrome. Stem Cell Reports. 2017 05 09;8(5):1155-1163 Authors: Iizuka-Koga M, Asashima H, Ando M, Lai CY, Mochizuki S, Nakanishi M, Nishimura T, Tsuboi H, Hirota T, Takahashi H, Matsumoto I, Otsu M, Sumida T Abstract Although it is important to clarify the pathogenic functions of T cells in human samples, their examination is often limited due to difficulty in obtaining sufficient numbers of dendritic cells (DCs), used as antigen-presenting cells, especially in autoimmune diseases. We describe the generation of DCs from induced pluripotent stem cells derived from T cells (T-iPSCs). We reprogrammed CD4+ T cell clones from a patient with Sjögren's syndrome (SS) into iPSCs, which were differentiated into DCs (T-iPS-DCs). T-iPS-DCs had dendritic cell-like morphology, and expressed CD11c, HLA-DR, CD80, CD86, and also BDCA-3. Compared with monocyte-derived DCs, the capacity for antigen processing was similar, and T-iPS-DCs induced the proliferative response of autoreactive CD4+ T cells. Moreover, we could evaluate T cell functions of the patient with SS. In conclusion, we obtained adequate numbers of DCs from T-iPSCs, which could be used to characterize pathogenic T cells in autoimmune diseases such as SS. PMID: 28494936 [PubMed - indexed for MEDLINE]
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Related Articles Yields and chondrogenic potential of primary synovial mesenchymal stem cells are comparable between rheumatoid arthritis and osteoarthritis patients. Stem Cell Res Ther. 2017 05 16;8(1):115 Authors: Kohno Y, Mizuno M, Ozeki N, Katano H, Komori K, Fujii S, Otabe K, Horie M, Koga H, Tsuji K, Matsumoto M, Kaneko H, Takazawa Y, Muneta T, Sekiya I Abstract BACKGROUND: Mesenchymal stem cells derived from the synovial membrane (synovial MSCs) are a candidate cell source for regenerative medicine of cartilage and menisci due to their high chondrogenic ability. Regenerative medicine can be expected for RA patients with the inflammation well-controlled as well as OA patients and transplantation of synovial MSCs would also be a possible therapeutic treatment. Some properties of synovial MSCs vary dependent on the diseases patients have, and whether or not the pathological condition of RA affects the chondrogenesis of synovial MSCs remains controversial. The purpose of this study was to compare the properties of primary synovial MSCs between RA and OA patients. METHODS: Human synovial tissue was harvested during total knee arthroplasty from the knee joints of eight patients with RA and OA respectively. Synovial nucleated cells were cultured for 14 days. Total cell yields, surface markers, and differentiation potentials were analyzed for primary synovial MSCs. RESULTS: Nucleated cell number per 1 mg synovium was 8.4 ± 3.9 thousand in RA and 8.0 ± 0.9 thousand in OA. Total cell number after 14-day culture/1 mg synovium was 0.7 ± 0.4 million in RA and 0.5 ± 0.3 million in OA, showing no significant difference between in RA and OA. Cells after 14-day culture were mostly positive for CD44, CD73, CD90, CD105, negative for CD45 both in RA and OA. There was no significant difference for the cartilage pellet weight and sGAG content per pellet between in RA and OA. Both oil red O-positive colony rate and alizarin red-positive colony rate were similar in RA and OA. CONCLUSIONS: Yields, surface markers and chondrogenic potential of primary synovial MSCs in RA were comparable to those in OA. Synovium derived from RA patients can be the cell source of MSCs for cartilage and meniscus regeneration. PMID: 28511664 [PubMed - indexed for MEDLINE]
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Related Articles Characteristics of Labial Gland Mesenchymal Stem Cells of Healthy Individuals and Patients with Sjögren's Syndrome: A Preliminary Study. Stem Cells Dev. 2017 08 15;26(16):1171-1185 Authors: Wang SQ, Wang YX, Hua H Abstract Sjögren's syndrome (SS) is a systemic autoimmune disease that is characterized by focal lymphocytic infiltration into exocrine organs such as salivary and lacrimal glands, resulting in dry mouth and eyes, and other systemic injuries. There is no curative clinical therapy for SS, and stem cell therapy has shown great potential in this area. The mesenchymal stem cells (MSCs) in the salivary glands of healthy individuals and in patients with SS have not been extensively studied. The aim of this study was to elucidate the characteristics of MSCs from the labial glands of healthy controls and of those from patients with SS to elucidate the related pathogenesis and to uncover potential avenues for novel clinical interventions. Labial glands from patients with SS and healthy subjects were obtained, and MSCs were isolated and cultured by using the tissue adherent method. The MSC characteristics of the cultured cells were confirmed by using morphology, proliferation, colony forming-unit (CFU) efficiency, and multipotentiality, including osteogenic, adipogenic, and salivary gland differentiation. The MSCs from the healthy controls and SS patients expressed characteristic MSC markers, including CD29, CD44, CD73, CD90, and CD105; they were negative for CD34, CD45, and CD106, and also negative for the salivary gland epithelium markers (CD49f and CD117). Labial gland MSCs from both groups were capable of osteogenic and adipogenic differentiation. The CFU efficiency and adipogenic differentiation potential of MSCs were significantly lower in the SS group compared with the healthy controls. Cells from both groups could also be induced into salivary gland-like cells. Real-time polymerase chain reaction and immunofluorescence staining showed that the gene and protein expression of AMY1, AQP5, and ZO-1 in cells from the SS group was lower than that in cells from the healthy group. Thus, MSCs from the labial glands in patients with SS could lack certain characteristics and functions, especially related to salivary secretion. These preliminary data provided insights that could lead to the development of novel therapeutic strategies for the treatment of SS. PMID: 28537471 [PubMed - indexed for MEDLINE]
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Related Articles Use of immune modulation by human adipose-derived mesenchymal stem cells to treat experimental arthritis in mice. Am J Transl Res. 2017;9(5):2595-2607 Authors: Zhang L, Wang XY, Zhou PJ, He Z, Yan HZ, Xu DD, Wang Y, Fu WY, Ruan BB, Wang S, Chen HX, Liu QY, Zhang YX, Liu Z, Wang YF Abstract Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammatory cell infiltration and joint erosion. Human adipose-derived mesenchymal stem cells (hASCs) have shown the capacity of suppressing effector T cell activation and inflammatory cytokine expression. We investigated whether hASCs play a therapeutic role in collagen-induced arthritis (CIA) by administering a single dose of hASCs in mice with established CIA. In vivo, a beneficial effect was observed following hASC infusion as shown by a marked decrease in the severity of arthritis. Human ASCs were detectable in the joints, and reduced levels of pro-inflammatory cytokines and increased levels of anti-inflammatory cytokines were observed in the sera of the hASC-treated mice. Furthermore, hASC treatment induced the expansion of regulatory T cells (Tregs) both in the peripheral blood and in the spleen tissues. In vitro, hASCs downregulated the production of proinflammatory cytokines TNF-α, IL-1β, and IL-6 in mouse macrophages stimulated with lipopolysaccharide and inhibited the proliferation of human primary T cells in response to mitogens. Thus hASCs represent a novel and effective therapeutic strategy for RA. PMID: 28560007 [PubMed]
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Related Articles Mesenchymal stem cells for treating autoimmune dacryoadenitis. Stem Cell Res Ther. 2017 06 05;8(1):126 Authors: Lu X, Wang X, Nian H, Yang D, Wei R Abstract Autoimmune dacryoadenitis, such as Sjögren syndrome, comprises multifactorial and complex diseases. Inflammation of the lacrimal gland plays a key role in the pathogenesis of diseases. Unfortunately, current treatment strategies, including artificial tears, anti-inflammatory drugs, punctual occlusion, and immunosuppressive drugs, are only palliative, and long-term administration of these strategies is associated with adverse effects that limit their utility. Hence, an effective and safe treatment for autoimmune dacryoadenitis is urgently needed. Mesenchymal stem cells (MSCs) have emerged as a promising tool for treating autoimmune dacryoadenitis, owing to their immunosuppressive properties, tissue repair functions, and powerful differentiation capabilities. A large number of studies have focused on the effect of MSCs on autoimmune diseases, such as autoimmune uveitis, inflammatory bowel disease, and collagen-induced arthritis, but few studies have, to date, unequivocally established the efficacy of MSCs for treating autoimmune dacryoadenitis. In this review, we discuss recent advances in MSC treatment for autoimmune dacryoadenitis. PMID: 28583168 [PubMed - indexed for MEDLINE]
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Related Articles Chemokine signals are crucial for enhanced homing and differentiation of circulating osteoclast progenitor cells. Arthritis Res Ther. 2017 06 15;19(1):142 Authors: Sucur A, Jajic Z, Artukovic M, Matijasevic MI, Anic B, Flegar D, Markotic A, Kelava T, Ivcevic S, Kovacic N, Katavic V, Grcevic D Abstract BACKGROUND: The peripheral blood (PB) monocyte pool contains osteoclast progenitors (OCPs), which contribute to osteoresorption in inflammatory arthritides and are influenced by the cytokine and chemokine milieu. We aimed to define the importance of chemokine signals for migration and activation of OCPs in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: PB and, when applicable, synovial fluid (SF) samples were collected from 129 patients with RA, 53 patients with PsA, and 110 control patients in parallel to clinical parameters of disease activity, autoantibody levels, and applied therapy. Receptors for osteoclastogenic factors (CD115 and receptor activator of nuclear factor-κB [RANK]) and selected chemokines (CC chemokine receptor 1 [CCR1], CCR2, CCR4, CXC chemokine receptor 3 [CXCR3], CXCR4) were determined in an OCP-rich subpopulation (CD3-CD19-CD56-CD11b+CD14+) by flow cytometry. In parallel, levels of CC chemokine ligand 2 (CCL2), CCL3, CCL4, CCL5, CXC chemokine ligand 9 (CXCL9), CXCL10, and CXCL12 were measured using cytometric bead array or enzyme-linked immunosorbent assay. Sorted OCPs were stimulated in culture by macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, and they were differentiated into mature osteoclasts that resorb bone. Selected chemokines (CCL2, CCL5, CXCL10, and CXCL12) were tested for their osteoclastogenic and chemotactic effects on circulatory OCPs in vitro. RESULTS: The OCP population was moderately enlarged among PB cells in RA and correlated with levels of tumor necrosis factor-α (TNF-α), rheumatoid factor, CCL2, and CCL5. Compared with PB, the RANK+ subpopulation was expanded in SF and correlated with the number of tender joints. Patients with PsA could be distinguished by increased RANK expression rather than total OCP population. OCPs from patients with arthritis had higher expression of CCR1, CCR2, CCR4, CXCR3, and CXCR4. In parallel, patients with RA had increased levels of CCL2, CCL3, CCL4, CCL5, CXCL9, and CXCL10, with significant elevation in SF vs PB for CXCL10. The subset expressing CXCR4 positively correlated with TNF-α, bone resorption marker, and rheumatoid factor, and it was reduced in patients treated with disease-modifying antirheumatic drugs. The CCR4+ subset showed a significant negative trend during anti-TNF treatment. CCL2, CCL5, and CXCL10 had similar osteoclastogenic effects, with CCL5 showing the greatest chemotactic action on OCPs. CONCLUSIONS: In our study, we identified distinct effects of selected chemokines on stimulation of OCP mobilization, tissue homing, and maturation. Novel insights into migratory behaviors and functional properties of circulatory OCPs in response to chemotactic signals could open ways to new therapeutic targets in RA. PMID: 28619088 [PubMed - indexed for MEDLINE]
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Related Articles Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target. Front Immunol. 2017;8:667 Authors: Tvedt THA, Ersvaer E, Tveita AA, Bruserud Ø Abstract Allogeneic stem cell transplantation is associated with a high risk of treatment-related mortality mainly caused by infections and graft-versus-host disease (GVHD). GVHD is characterized by severe immune dysregulation and impaired regeneration of different tissues, i.e., epithelial barriers and the liver. The balance between pro- and anti-inflammatory cytokine influences the risk of GVHD. Interleukin-6 (IL-6) is a cytokine that previously has been associated with pro-inflammatory effects. However, more recent evidence from various autoimmune diseases (e.g., inflammatory bowel disease, rheumatoid arthritis) has shown that the IL-6 activity is more complex with important effects also on tissue homeostasis, regeneration, and metabolism. This review summarizes the current understanding of how pro-inflammatory IL-6 effects exerted during the peritransplant period shapes T-cell polarization with enhancement of Th17 differentiation and suppression of regulatory T cells, and in addition we also review and discuss the results from trials exploring non-selective IL-6 inhibition in prophylaxis and treatment of GVHD. Emerging evidence suggests that the molecular strategy for targeting of IL-6-initiated intracellular signaling is important for the effect on GVHD. It will therefore be important to further characterize the role of IL-6 in the pathogenesis of GVHD to clarify whether combined IL-6 inhibition of both trans- (i.e., binding of the soluble IL-6/IL-6 receptor complex to cell surface gp130) and cis-signaling (i.e., IL-6 ligation of the IL-6 receptor/gp130 complex) or selective inhibition of trans-signaling should be tried in the prophylaxis and/or treatment of GVHD in allotransplant patients. PMID: 28642760 [PubMed]
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Related Articles Exploring the interplay between autoimmunity and cancer to find the target therapeutic hotspots. Artif Cells Nanomed Biotechnol. 2018 Jun;46(4):658-668 Authors: Kumar N, Chugh H, Tomar R, Tomar V, Singh VK, Chandra R Abstract Autoimmunity arises when highly active immune responses are developed against the tissues or substances of one's own body. It is one of the most prevalent disorders among the old-age population with prospects increasing with age. The major cause of autoimmunity and associated diseases is the dysregulation of host immune surveillance. Impaired repairment of immune system and apoptosis regulation can be seen as major landmarks in autoimmune disorders such as the mutation of p53 gene which results in rheumatoid arthritis, bowel disease which consequently lead to tissue destruction, inflammation and dysfunctioning of body organs. Cytokines mediated apoptosis and proliferation of cells plays a regulatory role in cell cycle and further in cancer development. Anti-TNF therapy, Treg therapy and stem cell therapy have been used for autoimmune diseases, however, with the increase in the use of immunomodulatory therapies and their development for autoimmune diseases and cancer, the understanding of human immune system tends to become an increasing requirement. Hence, the findings associated with the relationship between autoimmune diseases and cancer may prove to be beneficial for the improvement in the health of suffering patients. Here in, we are eliciting the underlying mechanisms which result in autoimmune disorders causing the onset of cancer, exploration of interactome to find the pathways which are mutual to both, and recognition of hotspots which might play important role in autoimmunity mediated therapeutics with different therapies such as anti-TNF therapy, Treg therapy and stem cell therapy. PMID: 28687059 [PubMed - indexed for MEDLINE]
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Related Articles Interleukin-3 enhances the migration of human mesenchymal stem cells by regulating expression of CXCR4. Stem Cell Res Ther. 2017 07 14;8(1):168 Authors: Barhanpurkar-Naik A, Mhaske ST, Pote ST, Singh K, Wani MR Abstract BACKGROUND: Mesenchymal stem cells (MSCs) represent an important source for cell therapy in regenerative medicine. MSCs have shown promising results for repair of damaged tissues in various degenerative diseases in animal models and also in human clinical trials. However, little is known about the factors that could enhance the migration and tissue-specific engraftment of exogenously infused MSCs for successful regenerative cell therapy. Previously, we have reported that interleukin-3 (IL-3) prevents bone and cartilage damage in animal models of rheumatoid arthritis and osteoarthritis. Also, IL-3 promotes the differentiation of human MSCs into functional osteoblasts and increases their in-vivo bone regenerative potential in immunocompromised mice. However, the role of IL-3 in migration of MSCs is not yet known. In the present study, we investigated the role of IL-3 in migration of human MSCs under both in-vitro and in-vivo conditions. METHODS: MSCs isolated from human bone marrow, adipose and gingival tissues were used for in-vitro cell migration, motility and wound healing assays in the presence or absence of IL-3. The effect of IL-3 preconditioning on expression of chemokine receptors and integrins was examined by flow cytometry and real-time PCR. The in-vivo migration of IL-3-preconditioned MSCs was investigated using a subcutaneous matrigel-releasing stromal cell-derived factor-1 alpha (SDF-1α) model in immunocompromised mice. RESULTS: We observed that human MSCs isolated from all three sources express IL-3 receptor-α (IL-3Rα) both at gene and protein levels. IL-3 significantly enhances in-vitro migration, motility and wound healing abilities of MSCs. Moreover, IL-3 preconditioning upregulates expression of chemokine (C-X-C motif) receptor 4 (CXCR4) on MSCs, which leads to increased migration of cells towards SDF-1α. Furthermore, CXCR4 antagonist AMD3100 decreases the migration of IL-3-treated MSCs towards SDF-1α. Importantly, IL-3 also induces in-vivo migration of MSCs towards subcutaneously implanted matrigel-releasing-SDF-1α in immunocompromised mice. CONCLUSIONS: The present study demonstrates for the first time that IL-3 has an important role in enhancing the migration of human MSCs through regulation of the CXCR4/SDF-1α axis. These findings suggest a potential role of IL-3 in improving the efficacy of MSCs in regenerative cell therapy. PMID: 28705238 [PubMed - indexed for MEDLINE]
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Related Articles The potential role of adult stem cells in the management of the rheumatic diseases. Ther Adv Musculoskelet Dis. 2017 Jul;9(7):165-179 Authors: Franceschetti T, De Bari C Abstract Adult stem cells are considered as appealing therapeutic candidates for inflammatory and degenerative musculoskeletal diseases. A large body of preclinical research has contributed to describing their immune-modulating properties and regenerative potential. Additionally, increasing evidence suggests that stem cell differentiation and function are disrupted in the pathogenesis of rheumatic diseases. Clinical studies have been limited, for the most part, to the application of adult stem cell-based treatments on small numbers of patients or as a 'salvage' therapy in life-threatening disease cases. Nevertheless, these preliminary studies indicate that adult stem cells are promising tools for the long-term treatment of rheumatic diseases. This review highlights recent knowledge acquired in the fields of hematopoietic and mesenchymal stem cell therapy for the management of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and osteoarthritis (OA) and the potential mechanisms mediating their function. PMID: 28717403 [PubMed]
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Related Articles Anti-arthritic activity of aqueous-methanolic extract and various fractions of Berberis orthobotrys Bien ex Aitch. BMC Complement Altern Med. 2017 Jul 18;17(1):371 Authors: Alamgeer, Uttra AM, Hasan UH Abstract BACKGROUND: The roots and stem bark of Berberis orthobotrys (Berberidaceae) have long been used traditionally to treat joint pain. Though, it has not been pharmacologically assessed for rheumatoid arthritis. The current study explores anti-arthritic activity and phytochemical analysis of aqueous-methanolic extract (30:70) and fractions (ethyl acetate, n-butanol, and aqueous) of Berberis orthobotrys roots. METHODS: Anti-arthritic potential was evaluated in vitro using protein denaturation (bovine serum albumin and egg albumin) and membrane stabilization methods at 12.5-800 μg/ml concentration and in vivo via turpentine oil, formaldehyde and Complete Freund Adjuvant (CFA) models at 50, 100 and 150 mg/kg doses. Also, in vitro antioxidant ability was appraised by reducing power assay. Moreover, total flavonoid content, Fourier transform infrared spectroscopy and High performance liquid chromatography of n-butanol fraction were performed. RESULTS: The results revealed concentration dependent inhibition of albumin denaturation and notable RBC membrane stabilization, with maximum results obtained at 800 μg/ml. Similarly, plant exhibited dose dependent anti-arthritic effect in turpentine oil and formaldehyde models, with maximum activity observed at 150 mg/kg. The results of CFA model depicted better protection against arthritic lesions and body weight alterations. Also, B.orthobotrys remarkably ameliorated altered hematological parameters, rheumatoid factor and positively modified radiographic and histopathological changes. Additionally, plant exhibited remarkable anti-oxidant activity. Moreover, phytochemical analysis revealed polyphenols and flavonoids. CONCLUSION: Taken together, these results support traditional use of B.orthobotrys as potent anti-arthritic agent that may be proposed for rheumatoid arthritis treatment. PMID: 28720131 [PubMed - indexed for MEDLINE]
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Related Articles Gastrin-releasing peptide and its receptor increase arthritis fibroblast-like synoviocytes invasiveness through activating the PI3K/AKT pathway. Peptides. 2017 Sep;95:57-61 Authors: Clarimundo VS, Farinon M, Pedó RT, Teixeira VON, Nör C, Gulko PS, Xavier RM, de Oliveira PG Abstract Rheumatoid arthritis (RA) is an autoimmune disease that leads to joint destruction. The fibroblast-like synoviocytes (FLS) has a central role on the disease pathophysiology. The present study aimed to examine the role of gastrin-releasing peptide (GRP) and its receptor (GRPR) on invasive behavior of mice fibroblast-like synoviocytes (FLS), as well as to evaluate GRP-induced signaling on PI3K/AKT pathway. The expression of GRPR in FLS was investigated by immunocytochemistry, western blot (WB) and qRT-PCR. The proliferation and invasion were assessed by SRB and matrigel-transwell assay after treatment with GRP and/or RC-3095 (GRPR antagonist), and/or Ly294002 (inhibitor of PI3K/AKT pathway). Finally, AKT phosphorylation was assessed by WB. GRPR protein was detected in FLS and the exposure to GRP increased FLS invasion by nearly two-fold, compared with untreated cells (p<0.05), while RC-3095 reversed that effect (p<0.001). GRP also increased phosphorylated AKT expression in FLS. When Ly294002 was added with GRP, it prevented the GRP-induced increased cell invasiveness (p<0.001). These data suggest that GRPR expression in FLS and that exogenous GRP are able to activate FLS invasion. This effect occurs at least in part through the AKT activation. Therefore, understanding of the GRP/GRPR pathway could be relevant in the development of FLS-targeted therapy for RA. PMID: 28733141 [PubMed - indexed for MEDLINE]
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Related Articles Leptin and autoimmune disease. Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(3):155-159 Authors: Fujita Y Abstract Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports. PMID: 28747601 [PubMed - indexed for MEDLINE]
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Related Articles Role of glucocorticoid-induced leucine zipper (GILZ) in inflammatory bone loss. PLoS One. 2017;12(8):e0181133 Authors: Yang N, Baban B, Isales CM, Shi XM Abstract TNF-α plays a key role in the development of rheumatoid arthritis (RA) and inflammatory bone loss. Unfortunately, treatment of RA with anti-inflammatory glucocorticoids (GCs) also causes bone loss resulting in osteoporosis. Our previous studies showed that overexpression of glucocorticoid-induced leucine zipper (GILZ), a mediator of GC's anti-inflammatory effect, can enhance osteogenic differentiation in vitro and bone acquisition in vivo. To investigate whether GILZ could antagonize TNF-α-induced arthritic inflammation and protect bone in mice, we generated a TNF-α-GILZ double transgenic mouse line (TNF-GILZ Tg) by crossbreeding a TNF-α Tg mouse, which ubiquitously expresses human TNF-α, with a GILZ Tg mouse, which expresses mouse GILZ under the control of a 3.6kb rat type I collagen promoter fragment. Results showed that overexpression of GILZ in bone marrow mesenchymal stem/progenitor cells protected mice from TNF-α-induced inflammatory bone loss and improved bone integrity (TNF-GILZ double Tg vs. TNF-αTg, n = 12-15). However, mesenchymal cell lineage restricted GILZ expression had limited effects on TNF-α-induced arthritic inflammation as indicated by clinical scores and serum levels of inflammatory cytokines and chemokines. PMID: 28771604 [PubMed - indexed for MEDLINE]
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Related Articles Rheumatoid arthritis in review: Clinical, anatomical, cellular and molecular points of view. Clin Anat. 2018 Mar;31(2):216-223 Authors: Sharif K, Sharif A, Jumah F, Oskouian R, Tubbs RS Abstract Rheumatoid arthritis (RA) is the most common chronic autoimmune disease of the joints affecting close to 0.5-1.0% of the general population. Although the etiopathogenesis of RA remains elusive, the involvement of dendritic cells and type 17 T-helper cells appears to be pivotal in maintaining a state of chronic inflammation. RA is generally characterized by small joint involvement. A chronic inflammatory process leads to joint destruction and to tendon and ligament laxity and disintegration. These processes result in an imbalance of forces acting on the joints causing joint deformities including swan neck deformity, boutonniere deformity of the hands, flexion deformity of the wrist, lesser toe deformities, and others. In some instances, bony erosions subsequent to the RA disease process can result in life-threatening events including, for example, atlanto-axial subluxation, which can cause myelopathy and paralysis; and basilar invagination, which can cause brain stem injury and imminent death. Although less commonly involved, larger joints are not spared, as evidenced by the involvement of the elbow, hip, and shoulder joints in a sizable proportion of RA patients. The progression and prognosis of this disease entity are variable, guarded and dependent on the efficacy and response to treatment modalities employed. Inadequate management results in disease progression, which ultimately leads to joint erosion, destruction, deformities and substantial decrease in the functional quality of life. Clin. Anat. 31:216-223, 2018. © 2017 Wiley Periodicals, Inc. PMID: 28833647 [PubMed - indexed for MEDLINE]
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Related Articles Anti-nociceptive and anti-inflammatory effects of the methanolic extract of Opuntia humifusa stem. Avicenna J Phytomed. 2017 Jul-Aug;7(4):366-375 Authors: Sharma BR, Park CM, Choi JW, Rhyu DY Abstract OBJECTIVE: Opuntia humifusa (O. humifusa) Raf. has been used for the prevention and treatment of rheumatoid arthritis, inflammation, and cancer. Our study was designed to unveil the anti-nociceptive and anti-inflammatory effects of the methanolic extract of O. humifusa Raf stem (OHS). MATERIALS AND METHODS: The anti-nociceptive effect was measured by hot plate, acetic acid-induced writhing, and tail flick assays in mice and rats. Moreover, the anti-inflammatory effect was measured by vascular permeability and carrageenan and serotonin-induced paw edema tests in rats. Furthermore, anti-inflammatory effect was also measured using macrophage-like LPS-induced RAW 264.7 cells. RESULTS: OHS extract inhibited acetic acid-induced writhing (p<0.0001), and delayed the reaction time of mice to the hot plate-induced thermal stimulation (p<0.0001) and tail flick tests (p<0.05). OHS extract attenuated the carrageenan and serotonin-induced paw edema in rats (p<0.001). Similarly, OHS extract significantly decreased Evans blue concentration in acetic acid induced vascular permeability test (p<0.0001), revealing its strong anti-inflammatory effect. Finally, among four different fractions of OHS extract, n-butanol fraction strongly decreased NO production (p<0.0001) and iNOS expression in LPS-induced RAW 264.7 cells. CONCLUSION: Our results suggest that the methanolic extract of O. humifusa stem can be used to develop a therapeutic or supportive drug and/or functional food against pain and inflammation related diseases. PMID: 28884086 [PubMed]
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Related Articles Genome Engineering for Personalized Arthritis Therapeutics. Trends Mol Med. 2017 10;23(10):917-931 Authors: Adkar SS, Brunger JM, Willard VP, Wu CL, Gersbach CA, Guilak F Abstract Arthritis represents a family of complex joint pathologies responsible for the majority of musculoskeletal conditions. Nearly all diseases within this family, including osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, are chronic conditions with few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as arthritis. These technologies, together with cell reprogramming methods, including the use of induced pluripotent stem cells, provide a platform for human disease modeling. We summarize new evidence from genome-wide association studies and genomics that substantiates a genetic basis for arthritis pathogenesis. We also review the potential contributions of genome engineering in the development of new arthritis therapeutics. PMID: 28887050 [PubMed - indexed for MEDLINE]
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Related Articles Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm. Ann Vasc Surg. 2018 Feb;47:230-237 Authors: Wang SK, Green LA, Gutwein AR, Drucker NA, Motaganahalli RL, Fajardo A, Babbey CM, Murphy MP Abstract BACKGROUND: Abdominal aortic aneurysms (AAAs) are a major source of morbidity and mortality despite continuing advances in surgical technique and care. Although the inciting factors for AAA development continue to be elusive, accumulating evidence suggests a significant periaortic inflammatory response leading to degradation and dilation of the aortic wall. Previous human trials have demonstrated safety and efficacy of mesenchymal stem cells (MSCs) in the treatment of inflammation-related pathologies such as rheumatoid arthritis, graft versus host disease, and transplant rejection. Therefore, herein, we describe the Aortic Aneurysm Repression with Mesenchymal Stem Cells (ARREST) trial, a phase I investigation into the safety of MSC infusion for patients with small AAA and the cells' effects on modulation of AAA-related inflammation. METHODS: ARREST is a phase I, single-center, double-blind, randomized controlled trial (RCT) investigating infusion both dilute and concentrated MSCs compared to placebo in 36 small AAA (35-45 mm) patients. Subjects will be followed by study personnel for 12 months to ascertain incidence of adverse events, immune cell phenotype expression, peripheral cytokine profile, and periaortic inflammation. Maximum transverse aortic diameter will be assessed regularly for 5 years by a combination of computed tomography and duplex sonography. RESULTS: Four patients have thus far been enrolled, randomized, and treated per protocol. We anticipate the conclusion of the treatment phase within the next 24 months with ongoing long-term follow-up. CONCLUSIONS: ARREST will be pivotal in assessing the safety of MSC infusion and provide preliminary data on the ability of MSCs to favorably modulate the pathogenic AAA host immune response. The data gleaned from this phase I trial will provide the groundwork for a larger, phase III RCT which may provide the first pharmaceutical intervention for AAA. PMID: 28916304 [PubMed - indexed for MEDLINE]
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Related Articles Aire-deficient mice provide a model of corneal and lacrimal gland neuropathy in Sjögren's syndrome. PLoS One. 2017;12(9):e0184916 Authors: Chen FY, Lee A, Ge S, Nathan S, Knox SM, McNamara NA Abstract Sjögren's syndrome (SS) is a chronic, autoimmune exocrinopathy that leads to severe dryness of the mouth and eyes. Exocrine function is highly regulated by neuronal mechanisms but little is known about the link between chronic inflammation, innervation and altered exocrine function in the diseased eyes and exocrine glands of SS patients. To gain a better understanding of neuronal regulation in the immunopathogenesis of autoimmune exocrinopathy, we profiled a mouse model of spontaneous, autoimmune exocrinopathy that possess key characteristics of peripheral neuropathy experienced by SS patients. Mice deficient in the autoimmune regulator (Aire) gene developed spontaneous, CD4+ T cell-mediated exocrinopathy and aqueous-deficient dry eye that were associated with loss of nerves innervating the cornea and lacrimal gland. Changes in innervation and tear secretion were accompanied by increased proliferation of corneal epithelial basal cells, limbal expansion of KRT19-positive progenitor cells, increased vascularization of the peripheral cornea and reduced nerve function in the lacrimal gland. In addition, we found extensive loss of MIST1+ secretory acinar cells in the Aire -/- lacrimal gland suggesting that acinar cells are a primary target of the disease, Finally, topical application of ophthalmic steroid effectively restored corneal innervation in Aire -/- mice thereby functionally linking nerve loss with local inflammation in the aqueous-deficient dry eye. These data provide important insight regarding the relationship between chronic inflammation and neuropathic changes in autoimmune-mediated dry eye. Peripheral neuropathies characteristic of SS appear to be tightly linked with the underlying immunopathological mechanism and Aire -/- mice provide an excellent tool to explore the interplay between SS-associated immunopathology and peripheral neuropathy. PMID: 28926640 [PubMed - indexed for MEDLINE]
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Related Articles A new clerodane furano diterpene glycoside from Tinospora cordifolia triggers autophagy and apoptosis in HCT-116 colon cancer cells. J Ethnopharmacol. 2018 Jan 30;211:295-310 Authors: Sharma N, Kumar A, Sharma PR, Qayum A, Singh SK, Dutt P, Paul S, Gupta V, Verma MK, Satti NK, Vishwakarma R Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Tinospora cordifolia is a miraculous ayurvedic herb used in the treatment of innumerable diseases such as diabetes, gonorrhea, secondary syphilis, anaemia, rheumatoid arthritis, dermatological diseases, cancer, gout, jaundice, asthma, leprosy, in the treatment of bone fractures, liver & intestinal disorders, purifies the blood, gives new life to the whole body; (rejuvenating herb) and many more. Recent studies have revealed the anticancer potential of this plant but not much work has been done on the anticancer chemical constituents actually responsible for its amazing anticancer effects. This prompted us to investigate this plant further for new potent anticancer molecules. AIM OF THE STUDY: The present study was designed to isolate and identify new promising anticancer candidates from the aqueous alcoholic extract of T. cordifolia using bioassay-guided fractionation. MATERIALS AND METHODS: The structures of the isolated compounds were determined on the basis of spectroscopic data interpretation and that of new potent anticancer molecule, TC-2 was confirmed by a single-crystal X-ray crystallographic analysis of its corresponding acetate. The in vitro anti-cancer activity of TC-2 was evaluated by SRB assay and the autophagic activity was investigated by immunofluorescence microscopy. Annexin-V FITC and PI dual staining was applied for the detection of apoptosis. The studies on Mitochondrial Membrane potential and ROS (Reactive oxygen species) production were also done. RESULTS: Bioassay guided fractionation and purification of the aqueous alcoholic stem extract of Tinospora cordifolia led to the isolation of a new clerodane furano diterpene glycoside (TC-2) along with five known compounds i.e. cordifolioside A (β-D-Glucopyranoside,4-(3-hydroxy-1-propenyl)- 2,6-dimethoxyphenyl 3-O-D-apio-β-D-furanosyl) (TC-1), β-Sitosterol(TC-3), 2β,3β:15,16-Diepoxy- 4α, 6β-dihydroxy-13(16),14-clerodadiene-17,12:18,1-diolide (TC-4), ecdysterone(TC-5) and tinosporoside(TC-6). TC-2 emerged as a potential candidate for the treatment of colon cancer. CONCLUSION: The overall study on the bioassay guided isolation of T.cordifolia identified and isolated a new clerodane furano diterpenoid that exhibited anticancer activity via induction of mitochondria mediated apoptosis and autophagy in HCT116 cells. We have reported a promising future candidate for treating colon cancer. PMID: 28962889 [PubMed - indexed for MEDLINE]
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Related Articles Interleukin-34 Promotes Fibrocyte Proliferation. J Interferon Cytokine Res. 2017 Oct;37(10):440-448 Authors: Galligan CL, Fish EN Abstract Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting multiple joints. It remains unclear which factors in the circulation are associated with the systemic spread of the disease. Fibrocytes are pluripotent mesenchymal stem cells present in the circulation of RA patients. Our earlier findings implicated activated fibrocytes in the etiology of onset and pathogenesis of RA. Elevated levels of interleukin-34 (IL-34) in the serum and synovial fluid of RA patients are associated with rheumatoid factor and anticyclic citrullinated peptide antibodies, indicators of RA. Moreover, IL-34 levels are independent predictors of radiographic progression in RA patients. We provide evidence of simultaneous elevated levels of IL-34 and increased numbers of activated fibrocytes in the circulation of mice induced to develop arthritis. In vitro, IL-34 treatment induced the proliferation of fibrocytes, mediated by activation of cognate CSF-R1s on fibrocytes. Taken together, we infer that IL-34 has a role in stimulating fibrocyte proliferation and activation during arthritis, thereby contributing to both onset of RA and systemic spread of disease. PMID: 28972432 [PubMed - indexed for MEDLINE]
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Related Articles Functional genomics of stromal cells in chronic inflammatory diseases. Curr Opin Rheumatol. 2018 Jan;30(1):65-71 Authors: Slowikowski K, Wei K, Brenner MB, Raychaudhuri S Abstract PURPOSE OF REVIEW: Stroma is a broad term referring to the connective tissue matrix in which other cells reside. It is composed of diverse cell types with functions such as extracellular matrix maintenance, blood and lymph vessel development, and effector cell recruitment. The tissue microenvironment is determined by the molecular characteristics and relative abundances of different stromal cells such as fibroblasts, endothelial cells, pericytes, and mesenchymal precursor cells. Stromal cell heterogeneity is explained by embryonic developmental lineage, stages of differentiation to other cell types, and activation states. Interaction between immune and stromal cell types is critical to wound healing, cancer, and a wide range of inflammatory diseases. Here, we review recent studies of inflammatory diseases that use functional genomics and single-cell technologies to identify and characterize stromal cell types associated with pathogenesis. RECENT FINDINGS: High dimensional strategies using mRNA sequencing, mass cytometry, and fluorescence activated cell-sorting with fresh primary tissue samples are producing detailed views of what is happening in diseased tissue in rheumatoid arthritis, inflammatory bowel disease, and cancer. Fibroblasts positive for CD90 (Thy-1) are enriched in the synovium of rheumatoid arthritis patients. Single-cell RNA-seq studies will lead to more discoveries about the stroma in the near future. SUMMARY: Stromal cells form the microenvironment of inflamed and diseased tissues. Functional genomics is producing an increasingly detailed view of subsets of stromal cells with pathogenic functions in rheumatic diseases and cancer. Future genomics studies will discover disease mechanisms by perturbing molecular pathways with chemokines and therapies known to affect patient outcomes. Functional genomics studies with large sample sizes of patient tissues will identify patient subsets with different disease phenotypes or treatment responses. PMID: 28984647 [PubMed - indexed for MEDLINE]
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Related Articles Origins of fibroblasts in rheumatoid synovial tissues: Implications from organ fibrotic models. Mod Rheumatol. 2018 Jul;28(4):579-582 Authors: Matsuo Y, Saito T, Yamamoto A, Kohsaka H Abstract Fibroblasts play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Accumulation of fibroblasts in the synovial tissues characterizes the pathology of RA. Understanding how fibroblasts accumulate could lead to discovery of new therapeutic targets in RA treatment, while current antirheumatic therapies still have problems in efficacy and safety. In this regard, several studies have revealed cellular origins of fibroblasts in fibrotic tissues in murine models of organ fibrosis. Some studies employed lineage tracing, which bring generally convincing results, using transgenic mice. They demonstrated that resident fibroblasts, pericytes, mesenchymal stem cells, epithelial cells, endothelial cells and bone-marrow-derived and circulating cells can be cellular origins of fibroblasts in organ fibrotic tissues. In this review, we summarize and discuss available evidence for the origins of fibroblasts accumulating in the arthritic synovial tissues and organ fibrotic tissues. PMID: 29067846 [PubMed - indexed for MEDLINE]
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Related Articles Chondral tissue engineering of the reumatoid knee with collagen matrix autologous chondrocytes implant. Acta Biomed. 2017 10 18;88(4S):107-113 Authors: Leigheb M, Bosetti M, De Consoli A, Borrone A, Cannas M, Grassi F Abstract Articular cartilage repair is still a challenge. To date evidence is insufficient to support a treatment over the others. Inflammatory conditions in the joint hamper the application of tissue engineering during chronic joint diseases. Most of the Matrix Autologous Chondrocyte Implantation (MACI) cases reported in literature do not deal with rheumatoid knees and do not have a long clinical-histologic follow-up. We report about a 46-year old woman who suffered of a painful focal Outerbridge 4th degree chondral lesion in the medial femoral condyle of her left rheumatoid knee. The tissue defect was filled by a Cartilage Regeneration System (CaReS®) based on a type I collagen matrix seeded by autologous in vitro expanded chondrocytes. The patient was followed up to ten years clinically and by MRI, and finally treated with a Total Knee Replacement for the increasing arthritis. Histologically, the explanted MACI tissue showed an increased cellularity with an extracellular matrix rich of collagen and glycosaminoglicanes even though the overall architecture was different from the normal cartilage pattern. The case reported suggests that the main goal of treatment for chondropathy is the long lasting control of symptoms, while permanent restoration of normal anatomy is still impossible. Mesenchymal stem cells, that develop into joint tissues, show immunosuppressive and anti-inflammatory qualities, in vitro and in vivo, indicating a potential role for tissue engineering approaches in the treatment of rheumatic diseases. PMID: 29083361 [PubMed - indexed for MEDLINE]
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Related Articles Manipulation of Panx1 Activity Increases the Engraftment of Transplanted Lacrimal Gland Epithelial Progenitor Cells. Invest Ophthalmol Vis Sci. 2017 11 01;58(13):5654-5665 Authors: Basova LV, Tang X, Umasume T, Gromova A, Zyrianova T, Shmushkovich T, Wolfson A, Hawley D, Zoukhri D, Shestopalov VI, Makarenkova HP Abstract Purpose: Sjögren's syndrome is a systemic chronic autoimmune inflammatory disease that primarily targets the salivary and lacrimal glands (LGs). Currently there is no cure; therefore, cell-based regenerative therapy may be a viable option. LG inflammation is facilitated by extracellular ATP and mediated by the Pannexin-1 (Panx1) membrane channel glycoprotein. We propose that suppression of inflammation through manipulation of Panx1 activity can stimulate epithelial cell progenitor (EPCP) engraftment. Methods: The expression of pannexins in the mouse and human LG was assayed by qRT-PCR and immunostaining. Acute LG inflammation was induced by interleukin-1α (IL1α) injection. Prior to EPCP transplantation, IL1α-injured or chronically inflamed LGs of thrombospondin-1-null mice (TSP-1-/-) were treated with the Panx1-specific blocking peptide (10panx) or the self-deliverable RNAi (sdRNAi). The efficacy of cell engraftment and the area of inflammation were analyzed by microscopy. Results: Panx1 and Panx2 were detected in the mouse and human LGs. Panx1 and proinflammatory factors were upregulated during acute inflammation at days 1 to 3 after the IL1α injection. The analysis of EPCP engraftment demonstrated a significant and reproducible positive correlation between the 10panx peptide or Panx1 sdRNAi treatment and the number of engrafted cells. Similarly, treatment of the LG of the TSP-1-/- mouse (mouse model of chronic LG inflammation) by either Panx1 or Caspase-4 (also known as Casp11) sdRNAi showed a significant decrease in expression of proinflammatory markers and the lymphocyte infiltration. Conclusions: Our results suggest that blocking Panx1 and/or Casp4 activities is a beneficial strategy to enhance donor cell engraftment and LG regeneration through the reduction of inflammation. PMID: 29098296 [PubMed - indexed for MEDLINE]
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Related Articles Modeling Mesenchymal Stem Cells in TMJ Rheumatoid Arthritis and Osteoarthritis Therapy. Crit Rev Eukaryot Gene Expr. 2017;27(3):205-210 Authors: Serakinci N, Savtekin G Abstract Stem cells have self-renewal capacity and an ability to differentiate into particular cell types generating mature cells. Mesenchymal stem cells (MSCs) have a significant role in tissue homeostasis, which leads into tissue regeneration. MSCs are rare pluripotent cells supporting hematopoietic and mesenchymal cell lineages. MSCs are also believed to have therapeutic power over temporomandibular joint (TMJ) disorders (TMDs). The most common type of TMD is articular disc displacement, which induces progressive degenerative changes. These changes lead to rheumatoid arthritis or osteoarthritis. In this review, use of human mesenchymal cells (hMSCs) for therapeutic treatment of inflammatory diseases of TMJ is discussed. PMID: 29199605 [PubMed - indexed for MEDLINE]
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Related Articles Articular and subcutaneous adipose tissues of rheumatoid arthritis patients represent equal sources of immunoregulatory mesenchymal stem cells. Autoimmunity. 2017 Dec;50(8):441-450 Authors: Skalska U, Kuca-Warnawin E, Kornatka A, Janicka I, Musiałowicz U, Burakowski T, Kontny E Abstract Adipose-derived mesenchymal stem cells (ASCs) have immunoregulatory properties, but their activity is dependent on signals provided by the local microenvironment. It is likely that highly inflammatory milieu of rheumatoid joint affects ASCs activity. To test this hypothesis, the function of rheumatoid ASCs derived from articular adipose tissue (AT-ASCs) and ASCs derived from subcutaneous adipose tissue (Sc-ASCs) has been analysed. Articular adipose tissue (infrapatellar fat pad) and subcutaneous adipose tissue (from the site of skin closure with sutures) were obtained from rheumatoid arthritis (RA) patients undergoing total knee joint replacement surgery. ASCs were isolated accordingly to the routinely applied procedure, expanded and treated or not with IFNγ and TNF (10 ng/ml). To evaluate immunomodulatory properties of AT- and Sc-ASCs, co-cultures with peripheral blood mononuclear cells (PBMCs) from healthy donors have been set. Proliferation of activated PBMCs (3H-thymidine incorporation method), secretion of IL-10 and IL-17A in co-culture supernatants (specific ELISA tests) and T regulatory FoxP3+ cells (Tregs) percentage have been evaluated (flow cytometry). Performed experiments demonstrated that ASCs from both sources have comparable properties. They suppress proliferation of activated PBMCs to the similar extent, induce IL-10 secretion by resting PBMCs and moderately induce generation of FoxP3+ Treg cells. Interestingly, both AT-ASCs and Sc-ASCs cause increase of IL-17A secretion by activated PBMCs as well as induce up-regulation of IL-6 concentration in co-culture supernatants. We demonstrated that AT-ASCs and Sc-ASCs obtained from RA patients possess similar immunomodulatory properties despite different localization and distinct cytokine milieu of tissue of origin. Our results indicate that ASCs derived from rheumatoid adipose tissues are not strongly immunosuppressive in vitro and that they may contribute to the pathogenesis of RA due to IL-17A secretion enhancement. PMID: 29212384 [PubMed - indexed for MEDLINE]
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Related Articles Effects of sesamin on primary human synovial fibroblasts and SW982 cell line induced by tumor necrosis factor-alpha as a synovitis-like model. BMC Complement Altern Med. 2017 Dec 13;17(1):532 Authors: Khansai M, Phitak T, Klangjorhor J, Udomrak S, Fanhchaksai K, Pothacharoen P, Kongtawelert P Abstract BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic synovitis, cartilage degradation and bone deformities. Synovitis is the term for inflammation of the synovial membrane, an early stage of RA. The pathogenesis of the disease occurs through cytokine induction. The major cytokine that increases the severity of RA is TNF-α. Thus, inhibition of the TNF-α cascade is an effective way to diminish the progression of the disease. We are interested in investigating the difference between primary human synovial fibroblast (hSF) cells and SW982 as synovitis models induced by TNF-α and in monitoring their responses to sesamin as an anti-inflammatory phytochemical. METHOD: The designed experiments were performed in hSF cells or the SW982 cell line treated with 10 ng/ml TNF-α with or without 0.25, 0.5 or 1 μM sesamin. Subsequently, pro-inflammatory cytokine genes and proteins were measured in parallel with a study of associated signalling transduction involved in inflammatory processes, including NF-κB and MAPK pathways. RESULTS: The results demonstrated that although hSF and SW982 cells responded to TNF-α induction in the same fashion, they reacted at different levels. TNF-α could induce IL-6, IL-8 and IL-1β in both cell types, but the levels in SW982 cells were much higher than in hSF cells. This characteristic was due to the different induction of MAPKs in each cell type. Both cell types reacted to sesamin in almost the same fashion. However, hSF cells were more sensitive to sesamin than SW982 cells in terms of the anti-RA effect. CONCLUSIONS: The responses of TNF-α-induced hSF and SW982 were different at the signal transduction level. However, the two cell types showed almost the same reaction to sesamin treatment in terms of the end point of the response. PMID: 29237438 [PubMed - indexed for MEDLINE]
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Related Articles [Inflammation and osteoclasts]. Nihon Rinsho Meneki Gakkai Kaishi. 2017;40(5):367-376 Authors: Yokota K Abstract   Osteoclasts are differentiated from precursors of the monocyte/macrophage lineage originated from bone marrow hematopoietic stem cells and are the sole bone-resorbing cells in the body. Osteoclast differentiation is thought to require M-CSF (macrophage colony-stimulating factor) and RANKL (receptor activator of nuclear factor kappa-B ligand) signaling. However, it has recently been proposed that under chronic inflammatory conditions, such as systemic autoimmune diseases (e.g., rheumatoid arthritis), an increase in inflammatory cytokine levels within joints induces pathological osteoclast differentiation, causing excessive bone resorption. In addition, the authors have reported that stimulating mouse bone marrow monocytes and human CD14+ monocytes with combination of TNFα and IL-6 can induce differentiation of osteoclast-like cells, which are cells with bone resorption activity. In the present article, we discuss the mechanism of osteoclast differentiation of RANKL-independent bone-resorbing cells, using both data from the aforementioned report as well as the latest findings. Understanding the mechanisms underlying RANKL-independent, cytokine-mediated osteoclast differentiation could facilitate the development of novel therapies for inflammatory joint diseases. PMID: 29238019 [PubMed - indexed for MEDLINE]
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Related Articles Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study. Mod Rheumatol. 2018 Sep;28(5):858-864 Authors: Kirino Y, Kawaguchi Y, Tada Y, Tsukamoto H, Ota T, Iwamoto M, Takahashi H, Nagasawa K, Takei S, Horiuchi T, Ichida H, Minota S, Ueda A, Ohta A, Ishigatsubo Y Abstract BACKGROUND: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria. PMID: 29278009 [PubMed - indexed for MEDLINE]
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Related Articles Serum components and clinical efficacies of autologous serum eye drops in dry eye patients with active and inactive Sjogren syndrome. Taiwan J Ophthalmol. 2017 Oct-Dec;7(4):213-220 Authors: Ma IH, Chen LW, Tu WH, Lu CJ, Huang CJ, Chen WL Abstract PURPOSE: Autologous serum eye drops are considered safe and efficient for the treatment of various ocular surface disorders, including dry eye diseases (DED) caused by the primary and secondary Sjogren syndrome (SS). However, the serum components in patients of SS may be different from those of normal patients and can thus lead to unpredictable therapeutic effects. This study divided the SS patients into active and inactive types based on the erythrocyte sedimentation rate and the presence or absence of active rheumatoid arthritis. METHODS: We compared the serum components of these two groups with standard and multiplex enzyme linked immunosorbent assay arrays and predicted the therapeutic effects of topical autologous serum for the treatment of DED with ocular surface disease index (OSDI) and Oxford Schema scale (OSS). RESULTS: Hyaluronic acid and transforming growth factor b1 levels were significantly higher in the active SS group compared to the inactive SS group (P < 0.01), whereas epidermal growth factors, insulin growth factor 1, and fibroblast growth factor b had no significant differences between these two groups. Active SS group had significantly higher expressions of interleukin (IL) 1 beta, IL 6, and tumor necrosis factor alpha compared to inactive SS patients (P < 0.05). There were no statistical differences in therapeutic effects between these two groups, as measured with the OSDI or OSS. CONCLUSION: Dividing the Sjogren dry eye patients into active and inactive groups may appear as a reasonable method to predict the quality of autologous serum eye drops, but there seems to be no significant predictability to the therapeutic effects. PMID: 29296554 [PubMed]
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Related Articles Umbilical cord blood stem cell treatment for a patient with psoriatic arthritis. World J Stem Cells. 2017 Dec 26;9(12):235-240 Authors: Coutts M, Soriano R, Naidoo R, Torfi H Abstract Clinical and laboratory results document psoriatic arthritis in a 56-year old patient. The symptoms did not resolve with standard treatments (nonsteroidal anti-inflammatory drugs, steroids and methotrexate). TNF-alpha inhibitors (certolizumab pegol and adalimumab) were added to the treatment regime, with some adverse effects. A trial of human umbilical cord stem cell therapy was then initiated. The stem cells were enriched and concentrated from whole cord blood, by removal of erythrocytes and centrifugation. The patient received several infusions of cord blood stem cells, through intravenous and intra-articular injections. These stem cell treatments correlated with remission of symptoms (joint pain and psoriatic plaques) and normalized serologic results for the inflammatory markers C-reactive protein and erythrocyte sedimentation rate. These improvements were noted within the first thirty days post-treatment, and were sustained for more than one year. The results of this trial suggest that cord blood stem cells may have important therapeutic value for patients with psoriatic arthritis, particularly for those who cannot tolerate standard treatments. PMID: 29321825 [PubMed]
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Related Articles Loss of A20 in BM-MSCs regulates the Th17/Treg balance in Rheumatoid Arthritis. Sci Rep. 2018 01 11;8(1):427 Authors: Feng Z, Zhai Y, Zheng Z, Yang L, Luo X, Dong X, Han Q, Jin J, Chen ZN, Zhu P Abstract Mesenchymal stem cells (MSCs) are multi-potent cells that are self-renewable and possess the potential to differentiate into multiple lineages. Several studies demonstrated that MSCs could regulate a Th17/Treg balance and could be a potential therapeutic target for Rheumatoid Arthritis (RA). A20 is highly expressed in many cell types after the stimulation of TNF-α, where it may inhibit pro-inflammatory cytokine secretion. However, the expression of A20 in BM-MSCs in RA is not fully understood. In our study, we found that A20 was decreased in RA patients' bone marrow MSCs (BM-MSCs), and with more IL-6 secretion, the balance of Th17/Treg was broken. In CIA mice, we found a moderate A20 decrease in mice MSCs as compared with those of control group in mRNA and protein levels. However, the IL-6 expression was increased. After umbilical cord MSCs treatment, A20 and IL-6 expressions were equal to the control group. Thus, our study indicates that loss of A20 in MSCs regulates the Th17/Treg balance in RA and the regulatory role of A20 in pro-inflammatory IL-6 production could be a potential target for the transfer of MSCs in RA adoptive therapy. PMID: 29323140 [PubMed - indexed for MEDLINE]
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Related Articles The polymethoxy flavonoid sudachitin suppresses inflammatory bone destruction by directly inhibiting osteoclastogenesis due to reduced ROS production and MAPK activation in osteoclast precursors. PLoS One. 2018;13(1):e0191192 Authors: Ohyama Y, Ito J, Kitano VJ, Shimada J, Hakeda Y Abstract Inflammatory bone diseases, including rheumatoid arthritis, periodontitis and peri-implantitis, are associated not only with the production of inflammatory cytokines but also with local oxidative status, which is defined by intracellular reactive oxygen species (ROS). Osteoclast differentiation has been reported to be related to increased intracellular ROS levels in osteoclast lineage cells. Sudachitin, which is a polymethoxyflavone derived from Citrus sudachi, possesses antioxidant properties and regulates various functions in mammalian cells. However, the effects of sudachitin on inflammatory bone destruction and osteoclastogenesis remain unknown. In calvaria inflamed by a local lipopolysaccharide (LPS) injection, inflammation-induced bone destruction and the accompanying elevated expression of osteoclastogenesis-related genes were reduced by the co-administration of sudachitin and LPS. Moreover, sudachitin inhibited osteoclast formation in cultures of isolated osteoblasts and osteoclast precursors. However, sudachitin rather increased the expression of receptor activator of NF-κB ligand (RANKL), which is an important molecule triggering osteoclast differentiation, and the mRNA ratio of RANKL/osteoprotegerin that is a decoy receptor for RANKL, in the isolated osteoblasts, suggesting the presence of additional target cells. When osteoclast formation was induced from osteoclast precursors derived from bone marrow cells in the presence of soluble RANKL and macrophage colony-stimulating factor, sudachitin inhibited osteoclastogenesis without influencing cell viability. Consistently, the expression of osteoclast differentiation-related molecules including c-fos, NFATc1, cathepsin K and osteoclast fusion proteins such as DC-STAMP and Atp6v0d2 was reduced by sudachitin. In addition, sudachitin decreased activation of MAPKs such as Erk and JNK and the ROS production evoked by RANKL in osteoclast lineage cells. Our findings suggest that sudachitin is a useful agent for the treatment of anti-inflammatory bone destruction. PMID: 29342179 [PubMed - indexed for MEDLINE]
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Related Articles Leflunomide: A promising drug with good antitumor potential. Biochem Biophys Res Commun. 2018 02 05;496(2):726-730 Authors: Zhang C, Chu M Abstract Leflunomide, an inhibitor of dihydroorotase dehydrogenase and thereby pyrimidine synthesis, was approved for treatment of rheumatoid arthritis in 1998. During the following years, leflunomide was used in various preclinical studies as a potential cancer treatment; at the same time, more mechanisms underlying the anticancer effect of leflunomide were identified. Thus, leflunomide has been identified as a potent anticancer drug. This article summarizes the mechanisms as well as results of leflunomide in the evolving field of cancer therapy. PMID: 29357281 [PubMed - indexed for MEDLINE]
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Related Articles Bone marrow mesenchymal stem cells suppress IL-9 in adjuvant-induced arthritis. Autoimmunity. 2018 Feb;51(1):25-34 Authors: Abd Elhalem SS, Haggag NZ, El-Shinnawy NA Abstract Interleukin-9 (IL-9) has been shown to be upregulated in rheumatoid arthritis (RA). The exact role of IL-9 has not yet been effectively studied. Mesenchymal stem cells (MSCs) have shown a promising immunomodulatory role towards repairing cartilage and restoring joint function. One of the key problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is attributed to oxidative and inflammatory stresses at the injured sites. Hesperidin (Hsd), a flavanone present in citrus fruits, has been studied as potential therapeutic agents that have anti-oxidant and anti-inflammatory activities. The objective of this study is to evaluate the therapeutic paracrine action of bone marrow MSCs on the IL-9 level in adjuvant-induced arthritis (AIA) and the enhancement effect of Hsd on transplanted MSCs. Articular tissue inflammation and cartilage damage were assessed by histological scoring. Antinuclear autoantibodies, tumour necrosis factor-alpha (TNF-α), IL-9, IL-4, interferon gamma (IFN-δ), and transforming growth factor-beta1 (TGF-β1), as well as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) levels, were assessed in spleen tissue homogenates after treatment with MSCs either alone or combined with Hsd for 4 weeks in an AIA rat model. Results of this study confirmed that MSCs decreased IL-9 levels in AIA and provide novel insights into the application of Hsd on MSC-based treatments. Highlights Adjuvant-induced arthritis (AIA) is one of the most widely used models that has a great similarity to rheumatoid arthritis (RA). Few studies in recent years have estimated IL-9 in rheumatic diseases and it remains an understudied cytokine. For the first time, bone marrow mesenchymal stem cells (MSCs) therapy has a vital role in splenocytes IL-9 level and further studies are required. Combined therapy of MSCs with antioxidants as hesperidin (Hsd) can alleviate oxidative stress and enhance stem cells immunomodulatory action. PMID: 29359591 [PubMed - in process]
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Related Articles Elimination of stem-like cancer cell side-population by auranofin through modulation of ROS and glycolysis. Cell Death Dis. 2018 Jan 24;9(2):89 Authors: Hou GX, Liu PP, Zhang S, Yang M, Liao J, Yang J, Hu Y, Jiang WQ, Wen S, Huang P Abstract Cancer side-population (SP) represents a sub-population of stem-like cancer cells that have an important role in drug resistance due to their high expression of the ATP-binding cassette transporter ABCG2 involved in drug export. Auranofin (AF), a clinical drug of gold complex that is used in treatment of rheumatoid arthritis, has been reported inducing tumor antiproliferation. However, whether AF can impact SP cells remains unclear. Our study showed that AF caused a depletion of SP cells and a downregulation of stem cell markers, and impaired their ability to form tumor colonies in vitro and incidence to develop tumors in vivo of lung cancer cells. Reactive oxygen species (ROS) had an important role in mediating AF-induced depletion of SP cells, which could be reversed by antioxidant NAC. Further study revealed that AF could also cause ATP depletion by inhibition of glycolysis. The depletion of cellular ATP might impair the function of ABCG2 pump, leading to increased drug accumulation within the cells and thus enhancing anticancer activity of chemotherapeutic agents such as adriamycin. Synergistic effect of AF and adriamycin was demonstrated both in vitro and in vivo. Simultaneous increase of ROS and inhibition of glycolysis is a novel strategy to eliminate stem-like cancer cells. Combination of AF with adriamycin seems to be promising to enhance therapeutic effectiveness. PMID: 29367724 [PubMed - in process]
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Related Articles Immune modulatory effects of statins. Immunology. 2018 05;154(1):69-75 Authors: Zeiser R Abstract Despite major advances in recent years, immunosuppressive regimens for multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and graft-versus-host disease still have major adverse effects and immunomodulation rather than immune paralysis would be desirable. Statins inhibit the rate-limiting enzyme of the l-mevalonate pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase. It was shown that blocking the l-mevalonate pathway reduces inflammation through effects on downstream metabolites of the pathway including farnesylpyrophosphates and geranylgeranylpyrophosphates, which are essential for the attachment of GTPases like RhoA, Rac and Ras to the cell membrane. Therefore, l-mevalonate pathway downstream products play critical roles in the different steps of an immune response including immune cell activation, migration, cytokine production, immune metabolism and survival. This review discusses the relevance of the different metabolites for the immunomodulatory effect of statins and connects preclinical results with data from clinical studies that tested statins for the treatment of different inflammatory diseases. PMID: 29392731 [PubMed - indexed for MEDLINE]
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Related Articles Long term treatment by mesenchymal stem cells conditioned medium modulates cellular, molecular and behavioral aspects of adjuvant-induced arthritis. Cell Mol Biol (Noisy-le-grand). 2018 Jan 31;64(1):19-26 Authors: Nazemian V, Manaheji H, Sharifi AM, Zaringhalam J Abstract Neuroinflammation plays a crucial role in expression of symptoms of numerous autoimmune and neurodegenerative diseases such as pain during rheumatoid arthritis. Overproduction of pro-inflammatory cytokines and activation of intracellular signaling pathways have been strongly implicated in the generation of pathological pain states, particularly at central nervous system sites and induction of spinal neuroinflammatory symptoms. The wide ranges of research to define new therapeutic approaches, including neuroimmune-modulators like stem cells are in progress. Mesenchymal stem cells conditioned medium (MSC-CM) has anti-inflammatory factors which can regulate the immune responses. The aim of this study was to investigate the effect of administration of MSC-CM on behavioral, cellular and molecular aspects of adjuvant-induced arthritis in male Wistar rats. Complete Freund's adjuvant (CFA)-induced arthritis (AA) was caused by single subcutaneous injection of CFA into the rat's hind paw on day 0. MSC-CM was administered daily (i.p.) and during the 21 days of the study after injection. Hyperalgesia, Edema, Serum TNF-α levels and p38MAPK and NF-κB activities were assessed on days 0,7,14 and 21 of the study. The results of this study indicated the role of MSC-CM in reducing inflammatory symptoms, serum TNF-α levels and activity of intracellular signaling pathway factors during different phases of inflammation caused by CFA. It seems that MSC-CM treatment due to its direct effects on inhibition of intracellular signaling pathways and pro-inflammatory cytokines can alleviate inflammatory symptoms and pain during CFA-induced arthritis. PMID: 29412789 [PubMed - indexed for MEDLINE]
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Related Articles Extracellular vesicles: A new therapeutic strategy for joint conditions. Biochem Pharmacol. 2018 Jul;153:134-146 Authors: Tofiño-Vian M, Guillén MI, Alcaraz MJ Abstract Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions. PMID: 29427625 [PubMed - in process]
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Related Articles Intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells in rheumatoid arthritis patients with knee involvement: Results of a randomized, triple-blind, placebo-controlled phase 1/2 clinical trial. Cytotherapy. 2018 Apr;20(4):499-506 Authors: Shadmanfar S, Labibzadeh N, Emadedin M, Jaroughi N, Azimian V, Mardpour S, Kakroodi FA, Bolurieh T, Hosseini SE, Chehrazi M, Niknejadi M, Baharvand H, Gharibdoost F, Aghdami N Abstract BACKGROUND: In this study, we intend to assess the safety and tolerability of intra-articular knee implantation of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with rheumatoid arthritis (RA) and to determine the preliminary clinical efficacy data in this population. The trial registration numbers are as follows: Royan Institute Ethics Committee: AC/91/1133; NCT01873625. METHODS: This single-center, randomized, triple-blind, placebo-controlled phase 1/2 clinical trial randomized RA patients with knee involvement to receive either an intra-articular knee implantation of 40 million autologous bone marrow-derived MSCs per joint or normal saline (placebo). Patients were followed up for 12 months to assess therapy outcomes. RESULTS: A total of 30 patients, 15 in the MSC group and 15 in the placebo group, enrolled in this study. There were no adverse effects reported after MSC administration or during follow-up. Patients who received MSCs had superior findings according to the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analogue scale (VAS), time to jelling and pain-free walking distance. However, this improvement could not be significantly sustained beyond 12 months. The MSC group exhibited improved standing time (P = 0.01). In addition, the MSCs appeared to contribute to reductions in methotrexate and prednisolone use. CONCLUSION: Intra-articular knee implantation of MSCs appeared to be safe and well tolerated. In addition, we observed a trend toward clinical efficacy. These results, in our opinion, have justified the need for further investigations over an extended assessment period with larger numbers of RA patients who have knee involvement. PMID: 29428486 [PubMed - in process]
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Related Articles Sinomenine inhibits the inflammatory responses of human fibroblast-like synoviocytes via the TLR4/MyD88/NF-κB signaling pathway in rheumatoid arthritis. Pharmazie. 2017 Jun 01;72(6):355-360 Authors: Yao RB, Zhao ZM, Zhao LJ, Cai H Abstract Rheumatoid arthritis (RA) is a systemic autoimmune disorder mainly characterized by inflammation of the synovial tissue that can lead to destruction of bone and cartilage. Sinomenine is an alkaloid extracted from the stem of the Chinese medicinal plant Sinomenium acutum. It has been reported that sinomenine has immunosuppressive and anti-inflammatory properties. However, the molecular mechanism underlying the effect of sinominine on IL-1β-induced human RA fibroblast-like synoviocytes (RAFLS) is poorly understood. Therefore, in this study, we investigated the effect of sinomenine on the expression of inflammatory cytokines in IL-1β-treated human RAFLS in vitro and the underlying mechanism. RAFLS viability was evaluated using the MTS assay after sinomenine treatment. The levels of inflammatory cytokines were measured with ELISA, RT-PCR and western blot, respectively. The levels of TLR4 and its downstream signaling targets were determined by western blot analysis. We found that sinomenine suppressed not only NO and PGE2 production but also iNOS and COX-2 expression in IL-1β-induced RAFLS. It also inhibited the expression of TNF-α and IL-6 in IL-1β-stimulated RAFLS. Furthermore, sinomenine prevented IL-1β-induced TLR4, MyD88 and p-NF-κB p65 expression. Taken together, these results demonstrated that sinomenine prevented IL-1β-induced inflammation in human RAFLS at least in part by inhibiting the TLR4/MyD88/NF-κB signaling pathway, suggesting that sinomenine could be a potential agent in the treatment of RA. PMID: 29442025 [PubMed - indexed for MEDLINE]
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Related Articles Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome. J Allergy Clin Immunol. 2018 Nov;142(5):1605-1617.e4 Authors: Cervantes-Luevano KE, Caronni N, Castiello MC, Fontana E, Piperno GM, Naseem A, Uva P, Bosticardo M, Marcovecchio GE, Notarangelo LD, Cicalese MP, Aiuti A, Villa A, Benvenuti F Abstract BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. OBJECTIVE: Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. METHODS: We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. RESULTS: Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. CONCLUSIONS: These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS. PMID: 29447842 [PubMed - in process]
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Related Articles Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018;8(5):1399-1410 Authors: Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, Noël D Abstract Objectives: Mesenchymal stem cells (MSCs) release extracellular vesicles (EVs) that display a therapeutic effect in inflammatory disease models. Although MSCs can prevent arthritis, the role of MSCs-derived EVs has never been reported in rheumatoid arthritis. This prompted us to compare the function of exosomes (Exos) and microparticles (MPs) isolated from MSCs and investigate their immunomodulatory function in arthritis. Methods: MSCs-derived Exos and MPs were isolated by differential ultracentrifugation. Immunosuppressive effects of MPs or Exos were investigated on T and B lymphocytes in vitro and in the Delayed-Type Hypersensitivity (DTH) and Collagen-Induced Arthritis (CIA) models. Results: Exos and MPs from MSCs inhibited T lymphocyte proliferation in a dose-dependent manner and decreased the percentage of CD4+ and CD8+ T cell subsets. Interestingly, Exos increased Treg cell populations while parental MSCs did not. Conversely, plasmablast differentiation was reduced to a similar extent by MSCs, Exos or MPs. IFN-γ priming of MSCs before vesicles isolation did not influence the immunomodulatory function of isolated Exos or MPs. In DTH, we observed a dose-dependent anti-inflammatory effect of MPs and Exos, while in the CIA model, Exos efficiently decreased clinical signs of inflammation. The beneficial effect of Exos was associated with fewer plasmablasts and more Breg-like cells in lymph nodes. Conclusions: Both MSCs-derived MPs and Exos exerted an anti-inflammatory role on T and B lymphocytes independently of MSCs priming. However, Exos were more efficient in suppressing inflammation in vivo. Our work is the first demonstration of the therapeutic potential of MSCs-derived EVs in inflammatory arthritis. PMID: 29507629 [PubMed - in process]
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Related Articles Th1-Th17 Ratio as a New Insight in Rheumatoid Arthritis Disease. Iran J Allergy Asthma Immunol. 2018 Feb;17(1):68-77 Authors: Bazzazi H, Aghaei M, Memarian A, Asgarian-Omran H, Behnampour N, Yazdani Y Abstract The Th17, Th1 and dual Th17/Th1 cells are important players in rheumatoid arthritis (RA) disease. To assess their roles, the frequency and impact of these cells were investigated in patients with different disease activity. In 14 new cases and 41 established RA patients in comparison with 22 healthy controls, the percentages of Th17, Th1 and dual Th17/Th1 cells were determined by flow-cytometry and their correlations were investigated with disease activity score (DAS28). Moreover, serum levels of IL-6 and IL-17 as inducer and functional cytokines for Th17 were investigated. Finally, serum levels of anti citrullinated protein antibody (ACPA) and rheumatoid factor (RF) were assessed. Percentage of Th17 cells in RA patients were increased in comparison with healthy controls (p<0.01). In correlation with this finding, IL-17 and IL-6 cytokines in RA patients also increased (p<0.01). The Th1 cells in RA patients were less than healthy group (p<0.05) and showed negative correlation with disease activity (r=-0.328, p<0.01). Dual Th17/Th1 cell only in new cases of RA were more than healthy control groups (p<0.01). The Th1/Th17 ratio in RA patients is statistically different with healthy control group (p<0.01) and it has negative correlation with disease activity (r=-264, p<0.05). The levels of ACPA and RF were increased with disease progression. Decreasing of Th1/Th17 ratio in RA patient suggested a new paradigm in the field of autoimmune disease and indicated that imbalance or plasticity between these subsets can be important in progress, diagnosis and therapy of RA disease. PMID: 29512371 [PubMed - in process]
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Related Articles Transplantation and Alternatives to Treat Autoimmune Diseases. Adv Exp Med Biol. 2018;1089:59-72 Authors: Shende P, Rodrigues B, Gaud RS Abstract Transplantation is considered as one of the methods for the treatment of autoimmune diseases. There are different sorts of transplantation which improved the situation for the cure of different kinds of autoimmune diseases. Cord blood transplantation is favored over other transplant techniques. The propelled treatments incorporate interferon administrative elements and mesenchymal stromal cells for the management of immune system issue particularly in the treatment of rheumatoid joint inflammation. According to the studies conducted, it was proven that cord blood/UC mesenchymal cells along with DMARDs, without consistent organization expanded the level of administrative regulatory T-cells of the peripheral blood which might be a protected and huge technique for the treatment of patients experiencing rheumatoid joint inflammation. This review article focusses on different organ transplantation and alternative methods to treat autoimmune condition like rheumatoid arthritis. Using 3D printing and artificial intelligence are some of the recent trends that may be used for the management of autoimmune diseases. PMID: 29516308 [PubMed - in process]
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Related Articles Testing the potency of anti-TNF-α and anti-IL-1β drugs using spheroid cultures of human osteoarthritic chondrocytes and donor-matched chondrogenically differentiated mesenchymal stem cells. Biotechnol Prog. 2018 Jul;34(4):1045-1058 Authors: Žigon-Branc S, Barlič A, Knežević M, Jeras M, Vunjak-Novakovic G Abstract Inflammation plays a major role in progression of rheumatoid arthritis, a disease treated with antagonists of tumor necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β). New in vitro testing systems are needed to evaluate efficacies of new anti-inflammatory biological drugs, ideally in a patient-specific manner. To address this need, we studied microspheroids containing 10,000 human osteoarthritic primary chondrocytes (OACs) or chondrogenically differentiated mesenchymal stem cells (MSCs), obtained from three donors. Hypothesizing that this system can recapitulate clinically observed effects of anti-inflammatory drugs, spheroids were exposed to TNF-α, IL-1β, or to supernatant containing secretome from activated macrophages (MCM). The anti-inflammatory efficacies of anti-TNF-α biologicals adalimumab, infliximab, and etanercept, and the anti-IL-1β agent anakinra were assessed in short-term microspheroid and long-term macrospheroid cultures (100,000 OACs). While gene and protein expressions were evaluated in microspheroids, diameters, amounts of DNA, glycosaminoglycans, and hydroxiproline were measured in macrospheroids. The tested drugs significantly decreased the inflammation induced by TNF-α or IL-1β. The differences in potency of anti-TNF-α biologicals at 24 h and 3 weeks after their addition to inflamed spheroids were comparable, showing high predictability of short-term cultures. Moreover, the data obtained with microspheroids grown from OACs and chondrogenically differentiated MSCs were comparable, suggesting that MSCs could be used for this type of in vitro testing. We propose that in vitro gene expression measured after the first 24 h in cultures of chondrogenically differentiated MSCs can be used to determine the functionality of anti-TNF-α drugs in personalized and preclinical studies. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1045-1058, 2018. PMID: 29536646 [PubMed - in process]
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Related Articles Towards an arthritis flare-responsive drug delivery system. Nat Commun. 2018 04 03;9(1):1275 Authors: Joshi N, Yan J, Levy S, Bhagchandani S, Slaughter KV, Sherman NE, Amirault J, Wang Y, Riegel L, He X, Rui TS, Valic M, Vemula PK, Miranda OR, Levy O, Gravallese EM, Aliprantis AO, Ermann J, Karp JM Abstract Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA. PMID: 29615615 [PubMed - indexed for MEDLINE]
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Related Articles Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis. Blood Adv. 2018 04 10;2(7):777-786 Authors: M F Silva J, Ladomenou F, Carpenter B, Chandra S, Sedlacek P, Formankova R, Grandage V, Friswell M, Cant AJ, Nademi Z, Slatter MA, Gennery AR, Hambleton S, Flood TJ, Lucchini G, Chiesa R, Rao K, Amrolia PJ, Brogan P, Wedderburn LR, Glanville JM, Hough R, Marsh R, Abinun M, Veys P Abstract Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely. PMID: 29618462 [PubMed - in process]
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Related Articles T-614 Promotes Osteoblastic Cell Differentiation by Increasing Dlx5 Expression and Regulating the Activation of p38 and NF-κB. Biomed Res Int. 2018;2018:4901591 Authors: Song J, Liu H, Zhu Q, Miao Y, Wang F, Yang F, Cheng W, Xi Y, Niu X, He D, Chen G Abstract Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by bone loss. Degree of inflammation has been identified as an important initiator of skeletal damage in RA. Iguratimod (T-614) is an anti-inflammatory agent which has been reported to show the inhibitory effect of bone destruction in RA. However, the role of T-614 in osteoblast differentiation is still not clear. In this study, we intended to find the effect of T-614 on the osteogenesis process. We detected osteogenesis markers and transcription factors associated with osteoblastic lineage and bone formation in the culture of mesenchymal stem cells which differentiate osteoblast. The contents and activity of alkaline phosphatase, levels of collagen type I and bone gla protein, and calcium nodule formation were increased significantly after T-614 treated. Meanwhile, the mRNAs expressions of Osterix and Dlx5 were also found to be increased significantly by real-time PCR. The changes of levels of phosphorylation of p38 and NF-κB were also detected by Western blot. The results showed that T-614 promotes osteoblastic differentiation by increasing the expression of Osterix and Dlx5 and increasing the activation of P38. T-614 could advance the ectopic expression of NF-κB to suppress inflammation, which indirectly inhibits the damage of the osteoblasts. PMID: 29670900 [PubMed - indexed for MEDLINE]
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Related Articles In-patient outcomes of Hematopoietic Stem Cell Transplantation in Patients with Immune Mediated Inflammatory Diseases: A Nationwide Study. Sci Rep. 2018 May 01;8(1):6825 Authors: Mehta K, Jaiswal P, Briggs F, Faubion WA, Tabibian JH, Cominelli F, Dave M Abstract The impact of underlying immune-mediated inflammatory diseases (IMID) in patients undergoing hematopoietic stem cell transplant (HSCT) is unclear. Hematopoietic cell transplantation co-morbidity index (HCT-CI) is gaining acceptance as a reliable clinical method to score pre-transplant co-morbidities. Higher HCT-CI from a co-morbid IMID implies higher NRM. However, HCT-CI integrates many IMIDs with different pathogenesis and treatment together which may lead to spurious results. We performed a cross-sectional study using Nationwide Inpatient Sample dataset from 1998 to 2011 to compare the outcomes of HSCT in patients with different co-morbid IMIDs with patients without any co-morbid IMIDs. In both our multivariate and stringent matched-pair analysis, ulcerative colitis (UC) was associated with increased mortality while rheumatoid arthritis and psoriasis were associated with lower mortality as compared to no IMID group. Furthermore, in allogeneic HSCT subgroup, UC was associated with higher mortality and psoriasis was associated with lower mortality. In conclusion, we found that depending on the type of HSCT, each IMID has a different impact on outcomes of HSCT. Furthermore, UC patients had increased mortality if they had primary sclerosing cholangitis and had a higher risk of opportunistic infections like tuberculosis and cytomegalovirus suggesting the need for increased vigilance in this cohort. PMID: 29717163 [PubMed - in process]
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Related Articles Potential of iPSC-Derived Mesenchymal Stromal Cells for Treating Periodontal Disease. Stem Cells Int. 2018;2018:2601945 Authors: Hynes K, Bright R, Marino V, Ng J, Verma PJ, Gronthos S, Bartold PM Abstract Mesenchymal stromal cell-like populations have been derived from mouse-induced pluripotent stem cells (miPSC-MSC) with the capability for tissue regeneration. In this study, murine iPSC underwent differentiation towards an MSC-like immunophenotype. Stable miPSC-MSC cultures expressed the MSC-associated markers, CD73, CD105, and Sca-1, but lacked expression of the pluripotency marker, SSEA1, and hematopoietic markers, CD34 and CD45. Functionally, miPSC-MSC exhibited the potential for trilineage differentiation into osteoblasts, adipocytes, and chondrocytes and the capacity to suppress the proliferation of mitogen-activated splenocytes. The efficacy of miPSC-MSC was assessed in an acute inflammation model following systemic or local delivery into mice with subcutaneous implants containing heat-inactivated P. gingivalis. Histological analysis revealed less inflammatory cellular infiltrate within the sponges in mice treated with miPSC-MSC cells delivered locally rather than systemically. Assessment of proinflammatory cytokines in mouse spleens found that CXCL1 transcripts and protein were reduced in mice treated with miPSC-MSC. In a periodontitis model, mice subjected to oral inoculation with P. gingivalis revealed less bone tissue destruction and inflammation within the jaws when treated with miPSC-MSC compared to PBS alone. Our results demonstrated that miPSC-MSC derived from iPSC have the capacity to control acute and chronic inflammatory responses associated with the destruction of periodontal tissue. Therefore, miPSC-MSC present a promising novel source of stromal cells which could be used in the treatment of periodontal disease and other inflammatory systemic diseases such as rheumatoid arthritis. PMID: 29731776 [PubMed]
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Related Articles The Spleen as an Optimal Site for Islet Transplantation and a Source of Mesenchymal Stem Cells. Int J Mol Sci. 2018 May 07;19(5): Authors: Sakata N, Yoshimatsu G, Kodama S Abstract This review demonstrates the unique potential of the spleen as an optimal site for islet transplantation and as a source of mesenchymal stem cells. Islet transplantation is a cellular replacement therapy used to treat severe diabetes mellitus; however, its clinical outcome is currently unsatisfactory. Selection of the most appropriate transplantation site is a major factor affecting the clinical success of this therapy. The spleen has long been studied as a candidate site for islet transplantation. Its advantages include physiological insulin drainage and regulation of immunity, and it has recently also been shown to contribute to the regeneration of transplanted islets. However, the efficacy of transplantation in the spleen is lower than that of intraportal transplantation, which is the current representative method of clinical islet transplantation. Safer and more effective methods of islet transplantation need to be established to allow the spleen to be used for clinical transplantation. The spleen is also of interest as a mesenchymal stem cell reservoir. Splenic mesenchymal stem cells contribute to the repair of damaged tissue, and their infusion may thus be a promising therapy for autoimmune diseases, including type 1 diabetes mellitus and Sjogren&rsquo;s syndrome. PMID: 29735923 [PubMed - indexed for MEDLINE]
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Related Articles Cell therapies for refractory rheumatoid arthritis. Clin Exp Rheumatol. 2018 Sep-Oct;36(5):911-919 Authors: Liu R, Zhao P, Tan W, Zhang M Abstract Rheumatoid arthritis (RA), an autoimmune disease, is characterised by a persistent synovitis in the joints and systemic inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and disease-modifying antirheumatic drugs (DMARDs) are widely used to treat RA patients. However, a portion of patients still have inadequate response to traditional medications. Recently, cell-based therapies have become the focus, attracting more attention due to their potential for remission induction. Several immune-regulatory cell types, such as haematopoietic stem cells, mesenchymal stem cells and regulatory T cells have been defined as novel targets. In this paper, we have summarised and reviewed current clinical trials using cell-based therapeutic approaches for the treatment of RA. PMID: 29745893 [PubMed - in process]
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Related Articles The human CSF pain proteome. J Proteomics. 2019 Jan 06;190:67-76 Authors: Khoonsari PE, Ossipova E, Lengqvist J, Svensson CI, Kosek E, Kadetoff D, Jakobsson PJ, Kultima K, Lampa J Abstract Chronic pain represents one of the major medical challenges in the 21st century, affecting >1.5 billion of the world population. Overlapping and heterogenous symptoms of various chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms. We have here investigated proteins found in human CSF with respect to known "pain" genes and in a cohort of patients with dysfunctional pain (fibromyalgia, FM), inflammatory pain (rheumatoid arthritis patients, RA) and non-pain controls utilized semi-quantitative proteomics using mass spectrometry (MS) to explore quantitative differences between these cohorts of patients. We found that "pain proteins" detected in CSF using MS are typically related to synaptic transmission, inflammatory responses, neuropeptide signaling- and hormonal activity. In addition, we found ten proteins potentially associated with chronic pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins might be of importance for understanding the mechanisms of dysfunctional/inflammatory chronic pain and also for use as potential biomarkers. SIGNIFICANCE: Chronic pain is a common disease and it poses a large burden on worldwide health. Fibromyalgia (FM) is a heterogeneous disease of unknown etiology characterized by chronic widespread pain (CWP). The diagnosis and treatment of FM is based on the analysis of clinical assessments and no measurable biomarkers are available. Cerebrospinal fluid (CSF) has been historically considered as a rich source of biomarkers for diseases of nervous system including chronic pain. Here, we explore CSF proteome of FM patients utilizing mass spectrometry based quantitative proteomics method combined with multivariate data analysis in order to monitor the dynamics of the CSF proteome. Our findings in this exploratory study support notable presence of pain related proteins in CSF yet with specific domains including inflammatory responses, neuropeptide signaling- and hormonal activity. We have investigated molecular functions of significantly altered proteins and demonstrate presence of 176 known pain related proteins in CSF. In addition, we found ten proteins potentially associated with pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins are novel in the context of FM but are known to be involved in pain mechanisms including inflammatory response and signal transduction. These results should be of clear significance and interest for researchers and clinicians working in the field of pain utilizing human CSF and MS based proteomics. PMID: 29852297 [PubMed - in process]
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Related Articles Biocompatible Gold Nanoparticles Ameliorate Retinoic Acid-Induced Cell Death and Induce Differentiation in F9 Teratocarcinoma Stem Cells. Nanomaterials (Basel). 2018 Jun 01;8(6): Authors: Gurunathan S, Kim JH Abstract The unique properties of gold nanoparticles (AuNPs) have attracted much interest for a range of applications, including biomedical applications in the cosmetic industry. The current study assessed the anti-oxidative effect of AuNPs against retinoic acid (RA)-induced loss of cell viability; cell proliferation; expression of oxidative and anti-oxidative stress markers, pro- and anti-apoptotic genes, and differentiation markers; and mitochondrial dysfunction in F9 teratocarcinoma stem cells. AuNPs were prepared by reduction of gold salts using luteolin as a reducing and stabilizing agent. The prepared AuNPs were spherical in shape with an average diameter of 18 nm. F9 cells exposed to various concentrations of these AuNPs were not harmed, whereas cells exposed to RA exhibited a dose-dependent change in cell viability and cell proliferation. The RA-mediated toxicity was associated with increased leakage of lactate dehydrogenase, reactive oxygen species, increased levels of malondialdehyde and nitric oxide, loss of mitochondrial membrane potential, and a reduced level of ATP. Finally, RA increased the level of pro-apoptotic gene expression and decreased the expression of anti-apoptotic genes. Interestingly, the toxic effect of RA appeared to be decreased in cells treated with RA in the presence of AuNPs, which was coincident with the increased levels of anti-oxidant markers including thioredoxin, glutathione peroxidases, glutathione, glutathione disulfide, catalase, and superoxide dismutase. Concomitantly, AuNPs ameliorated the apoptotic response by decreasing the mRNA expression of p53, p21, Bax, Bak, caspase-3, caspase-9, and increasing the expressions of Bcl-2 and Bcl-Xl. Interestingly, AuNPs not only ameliorated oxidative stress but also induced differentiation in F9 cells by increasing the expression of differentiation markers including retinoic acid binding protein, laminin 1, collagen type IV, and Gata 6 and decreasing the expressions of markers of stem cell pluripotency including Nanog, Rex1, octamer-binding transcription factor 4, and Sox-2. These consistent cellular and biochemical data suggest that AuNPs could ameliorate RA-induced cell death and facilitate F9 cell differentiation. AuNPs could be suitable therapeutic agents for the treatment of oxidative stress-related diseases such as atherosclerosis, cancer, diabetes, rheumatoid arthritis, and neurodegenerative diseases. PMID: 29865197 [PubMed]
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Related Articles Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis. PLoS One. 2018;13(6):e0198740 Authors: Nam Y, Jung SM, Rim YA, Jung H, Lee K, Park N, Kim J, Jang Y, Park YB, Park SH, Ju JH Abstract It is unclear how systemic administration of mesenchymal stem cells (MSCs) controls local inflammation. The aim of this study was to evaluate the therapeutic effects of human MSCs on inflammatory arthritis and to identify the underlying mechanisms. Mice with collagen antibody-induced arthritis (CAIA) received two intraperitoneal injections of human bone marrow-derived MSCs. The clinical and histological features of injected CAIA were then compared with those of non-injected mice. The effect of MSCs on induction of regulatory T cells was examined both in vitro and in vivo. We also examined multiple cytokines secreted by peritoneal mononuclear cells, along with migration of MSCs in the presence of stromal cell-derived factor-1 alpha (SDF-1α) and/or regulated on activation, normal T cell expressed and secreted (RANTES). Sections of CAIA mouse joints and spleen were stained for human anti-nuclear antibodies (ANAs) to confirm migration of injected human MSCs. The results showed that MSCs alleviated the clinical and histological signs of synovitis in CAIA mice. Peritoneal lavage cells from mice treated with MSCs expressed higher levels of SDF-1α and RANTES than those from mice not treated with MSCs. MSC migration was more prevalent in the presence of SDF-1α and/or RANTES. MSCs induced CD4+ T cells to differentiate into regulatory T cells in vitro, and expression of FOXP3 mRNA was upregulated in the forepaws of MSC-treated CAIA mice. Synovial and splenic tissues from CAIA mice receiving human MSCs were positive for human ANA, suggesting recruitment of MSCs. Taken together, these results suggest that MSCs migrate into inflamed tissues and directly induce the differentiation of CD4+ T cells into regulatory T cells, which then suppress inflammation. Thus, systemic administration of MSCs may be a therapeutic option for rheumatoid arthritis. PMID: 29879214 [PubMed - indexed for MEDLINE]
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Related Articles Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model. Adv Clin Exp Med. 2018 Jul;27(7):873-880 Authors: Abdelmawgoud H, Saleh A Abstract BACKGROUND: Mesenchymal stem cells (MSCs) are of increased importance because of their capacity to counteract inflammation and suppress host immune responses. OBJECTIVES: The aim of the study was to compare the effectiveness of MSCs and hematopoietic stem cells (HSCs) in the treatment of rheumatoid arthritis (RA). MATERIAL AND METHODS: Paw swelling was assessed by measuring the thickness of the hind paws using a caliper. Cytokines - interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and IL-10 - and rheumatoid factor (RF) were measured using enzyme-linked immunosorbent assay (ELISA) kits. Oxidative stress biomarkers - malondialdehyde (MDA) and reduced glutathione (GSH) were assessed. Nuclear factor-kappaB (NF-κB) was detected by the western blot technique. Toll-like receptor-2 (TLR-2), matrix metalloproteinase-3 (MMP-3) and cartilage oligomeric matrix protein-1 (COMP-1) gene expression were assessed by the real-time quantitative analysis. Mesenchymal stem cells were isolated from the bone marrow (BM) of rats and HSCs were isolated from human umbilical cord blood (UCB). RESULTS: Paw edema, RA score, RF, cytokine assay, antioxidant state, NF-κB, TLR-2, MMP3, and COMP-1 showed improvement in the group that received MSCs compared to the group that received HSCs and the group that received methotrexate. CONCLUSIONS: Mesenchymal stem cells are very effective in reducing RA inflammation; they are superior to HSC and methotrexate treatment. Mesenchymal stem cells could become a better therapeutic opportunity for the treatment of RA. PMID: 29905411 [PubMed - indexed for MEDLINE]
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Related Articles Intra-articular Injections in the Treatment of Symptoms from Ankle Arthritis: A Systematic Review. Foot Ankle Int. 2018 Oct;39(10):1141-1150 Authors: Vannabouathong C, Del Fabbro G, Sales B, Smith C, Li CS, Yardley D, Bhandari M, Petrisor BA Abstract BACKGROUND: Intra-articular (IA) injections are commonly used to treat knee arthritis pain; however, whether their efficacy generalizes to ankle arthritis remains debatable. We aimed to evaluate the evidence for IA therapies in the management of this patient population. METHODS: We performed a literature search for observational and randomized controlled trials (RCTs). Treatments included corticosteroids (CS), hyaluronic acid (HA), platelet-rich plasma (PRP), and mesenchymal stem cells (MSC). We extracted study details, patient demographics, treatment characteristics, efficacy outcomes, and safety. When feasible, data from RCTs were meta-analyzed using a random-effects model and 95% confidence intervals (CIs) were calculated. A P value <.05 was considered statistically significant. RESULTS: We identified 27 studies (1085 patients). Ankle OA, rheumatoid arthritis (RA), and hemophilic arthropathy populations were examined. The majority of studies were observational (20 studies); the only RCTs were those evaluating HA. Case series demonstrated favorable results in terms of symptomatic relief with CS, HA, PRP, and MSC injections; however, the effects of CS may only be short term and the evidence on MSCs was limited to 1 study with 6 ankle OA patients. Pooled results (3 RCTs, 109 patients) suggested significantly improved Ankle Osteoarthritis Scale scores with HA over saline at 6 months, with a mean difference of 12.47 points (95% CI 1.18-23.77, P = .03). CONCLUSION: Evidence from small trials favors HA and PRP injections for the treatment of pain associated with ankle osteoarthritis. However, the relative efficacy of all injectable therapies is far from definitive and warrants further high-quality comparative trials. LEVEL OF EVIDENCE: Level III, systematic review. PMID: 29909689 [PubMed - in process]
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Related Articles Comparative study of methotrexate and human umbilical cord mesenchymal stem cell transplantation in the treatment of rheumatoid arthritis. J Biol Regul Homeost Agents. 2018 May-Jun;32(3):599-605 Authors: Wang YH, Yang ZQ, Zhu SF, Gao Y Abstract In this study, a collagen-induced arthritis (CIA) model was established to simulate rheumatoid arthritis (RA) using two intradermal injections of bovine type II collagen and Freund’s complete adjuvant mixture given at two-week intervals. Subsequently, the transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) was used to treat RA and the treatment efficacy, as well as the possible regulatory mechanism underlying hUC-MSC transplantation, was observed. During the study, forty rats were randomly divided into four groups and their blood samples were collected at different time points to measure levels of serum cartilage oligomeric matrix protein (COMP). Based on the symptoms and pathological features of the rats, a total success rate of 83% was achieved by the treatment. Furthermore, the improvement of joint symptoms was more obvious when methotrexate and MSC transplantation were used. In summary, it was concluded that MSC transplantation relieved the symptoms of arthritis by down-regulating the expression of COMP on the synovial membrane and in the serum of CIA rats. PMID: 29921387 [PubMed - indexed for MEDLINE]
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Related Articles Effect of bone marrow mesenchymal stem cells on healing of temporomandibular joints in rats with induced rheumatoid arthritis. Eur J Oral Sci. 2018 Aug;126(4):272-281 Authors: El Qashty RMN, Mohamed NN, Radwan LRS, Ibrahim FMM Abstract The healing capacity of bone marrow mesenchymal stem cells (BMMSCs) has been evaluated in various studies. This study aimed to evaluate the effect of BMMSCs on the healing of temporomandibular joints (TMJs) with induced rheumatoid arthritis. Fifty healthy male Sprague Dawley rats were divided into three groups: group I (n = 10), negative control; group II (n = 20), positive control (induction of arthritis by adjuvant followed by intravenous injection of 0.1 ml of PBS); and group III (n = 20), intervention (as for group II but injected intravenously with 1 × 106  cells ml-1 of BMMSCs suspended in PBS). Half of the rats in each group were euthanized 3 wk after the start of the experiment and the other half was euthanized after 5 wk. Group I revealed normal TMJ features. Group II showed thickening of disc, thinning of cartilage, disordered bone trabeculae, and decreased in mean % area staining positive of collagen fibers at 3 wk, while at 5 wk these effects were more aggravated. Group III showed nearly normal thickness of disc and condylar cartilage, nearly normal arrangement of bone trabeculae and regenerated collagen fibers at 3 wk, while after 5 wk the TMJ features were almost normal. Two-way anova revealed statistically significant differences between groups. Thus, treatment of induced rheumatoid arthritis with BMMSCs shows promising results that need to be further investigated in humans. PMID: 29952027 [PubMed - in process]
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Related Articles Upregulation of chemokine CXCL10 enhances chronic pulmonary inflammation in tree shrew collagen-induced arthritis. Sci Rep. 2018 Jul 03;8(1):9993 Authors: Gao B, Lin J, Jiang Z, Yang Z, Yu H, Ding L, Yu M, Cui Q, Dunavin N, Zhang M, Li M Abstract Chronic pulmonary inflammation (CPI) gives rise to serious lung injuries in rheumatoid arthritis (RA) patients. However, the molecular mechanism underlying the pathogenesis of RA-associated CPI remains little understood. Here we established a novel tree shrew-based collagen-induced arthritis (TsCIA) model to study RA-associated CPI. Our results showed that typical CPI but not fibrosis developed pathologically in the TsCIA model. Furthermore, abnormal up-regulation of pulmonary chemokine CXCL10 was directly associated with lung damage. Specific blockage of CXCR3 (a CXCL10 receptor) significantly decreased the severity of CPI by decreasing the recruitment of inflammatory cells. Therefore, CXCL10 is proposed as a key player responsible for the development of TsCIA-associated CPI. Our findings also suggest that CXCR3 could be developed as a potential diagnosis biomarker for RA-associated CPI. PMID: 29968810 [PubMed - in process]
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Related Articles Emerging Role of Exosomes in the Joint Diseases. Cell Physiol Biochem. 2018;47(5):2008-2017 Authors: Li Z, Wang Y, Xiao K, Xiang S, Li Z, Weng X Abstract Exosomes are a subset of small, membrane-bound extracellular vesicles that are important for communication among cells. They originate from the cell membrane during endocytic internalization, and are stable in biological fluids, including blood and synovial fluids. Increasing knowledge is emerging about exosomes in joint diseases, including osteoarthritis, rheumatoid arthritis, osteonecrosis of the femoral head, and others. Exosomes in synovial fluid can lead to inflammation, degeneration of cartilage, and destruction of joints. Exosomes in blood have diagnostic value in the early disease stage or for complicated conditions of joint diseases. Exosomes from stem cells could delay diseases and repair joints. For a comprehensive understanding about the emerging role of exosomes in joint diseases, we introduced the isolation and verification of exosomes from synovial fluid, reviewed the physiological and pathological effects of exosomes on joints, and discussed the diagnostic value and therapeutic potential of exosomes in joint diseases. In the future, immunologically active exosomes and engineered exosomes will of interest in the joint diseases. Challenges in the field of exosomes in joint-disease research include complex and expensive isolation, detection of contributing molecular, effectiveness and safety evaluation. In summary, challenges remain, but the field of exosomes in joint diseases has potential, including in mechanisms, diagnoses and therapies. PMID: 29969758 [PubMed - indexed for MEDLINE]
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Related Articles Exosomes: mediators of bone diseases, protection, and therapeutics potential. Oncoscience. 2018 May;5(5-6):181-195 Authors: Behera J, Tyagi N Abstract Bone remodeling is a continuous lifelong process in the repair of micro-damage to bone architecture and replacement of aging tissue in bone. A failure to such process leads to pathological destructive bone diseases such as osteoporosis, rheumatoid arthritis, and osteoarthritis. However, this active process is regulated by; osteoclasts, which are involved in the bone resorption process; osteoblasts, with involvement in the bone formation process and bone-derived endothelial cells, which promote angiogenesis. In the bone micro-environment, these cellular interactions are mediated by a complex interplay between cell types via direct interaction of cell secreted growth factors, such as cytokines. Recently, the discovery of exosomes (∼ 40-100 nm in size), has attracted more attention in the field of the bone remodeling process. Exosomes and microvesicles are derived from different types of bone cells such as mesenchymal stem cells, osteoblasts, osteoclasts and their precursors. They are also recognized to play pivotal roles in bone remodeling processes including osteogenesis, osteoclastogenesis, and angiogenesis. In this review, we especially emphasize the origin and biogenesis of exosomes and bone cell derived exosomes in the regulatory process of bone remodeling. Moreover, this review article also focuses on exosomal secreted proteins and microRNAs and their involvement in the regulation of bone remodeling. PMID: 30035185 [PubMed]
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Related Articles Induced Pluripotent Stem Cells: The Most Versatile Source for Stem Cell Therapy. Clin Ther. 2018 Jul;40(7):1060-1065 Authors: Glicksman MA Abstract Cell therapy has existed since the first bone marrow transplant in the 1950s involving identical twins. The blood-forming stem cells were used to restore healthy blood cells for the twin with leukemia. It was not until 1968 that genetic matching (known as human leukocyte antigen matching) was known to be important, and not until 1973 that bone marrow transplants were performed from non-twin-related and nonrelated donors. The most important application of human stem cells is for the generation of cells and tissues for cell-based therapies. Currently, donated organs and tissues are often the only option to replace diseased, injured, or destroyed tissue. The availability for these transplantable tissues and organs is very limited, however. To satisfy the demand for a source for these cells and tissues, induced pluripotent stem cells that have been differentiated into specific cell types can serve as a renewable source of replacement cells and tissues. A bank of suitable human leukocyte antigen-matched cells will be an important source providing immediate availability of cells that are readily scalable, economical, and well characterized. Areas of active pursuit with stem cell therapy is being investigated for treating diseases such as macular degeneration, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, rheumatoid arthritis, and neurodegenerative diseases. This article describes the advantages and hurdles for the use of induced pluripotent cells as the starting material for a source of replacement cells for regenerative medicine. PMID: 30049501 [PubMed - in process]
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Related Articles History of autoimmune conditions and lymphoma prognosis. Blood Cancer J. 2018 Aug 01;8(8):73 Authors: Kleinstern G, Maurer MJ, Liebow M, Habermann TM, Koff JL, Allmer C, Witzig TE, Nowakowski GS, Micallef IN, Johnston PB, Inwards DJ, Thompson CA, Feldman AL, Link BK, Flowers C, Slager SL, Cerhan JR Abstract Autoimmune conditions are strong risk factors for developing lymphoma, but their role in lymphoma prognosis is less clear. In a prospective cohort study, we evaluated self-reported history of eight autoimmune conditions with outcomes in 736 diffuse large B-cell, 703 follicular, 302 marginal zone (MZL), 193 mantle cell (MCL), 297 Hodgkin lymphoma (HL), and 186 T-cell lymphomas. We calculated event-free survival (EFS) and overall survival (OS), and estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sex, prognostic score, and treatment. History of any of the eight autoimmune conditions ranged from 7.4% in HL to 18.2% in MZL, and was not associated with EFS or OS for any lymphoma subtype. However, there was a positive association of autoimmune conditions primarily mediated by B-cell responses with inferior EFS in MCL (HR = 2.23, CI: 1.15-4.34) and HL (HR = 2.63, CI: 1.04-6.63), which was largely driven by rheumatoid arthritis. Autoimmune conditions primarily mediated by T-cell responses were not found to be associated with EFS or OS in any lymphoma subtype, although there were few events for this exposure. Our results indicate that distinguishing autoimmune conditions primarily mediated by B-cell/T-cell responses may yield insight regarding the impact of this comorbid disease, affecting ~10% of lymphoma patients, on survival. PMID: 30069001 [PubMed - in process]
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Related Articles Epigenetic modification of mesenchymal stromal cells enhances their suppressive effects on the Th17 responses of cells from rheumatoid arthritis patients. Stem Cell Res Ther. 2018 Aug 09;9(1):208 Authors: Kim KW, Kim HJ, Kim BM, Kwon YR, Kim HR, Kim YJ Abstract BACKGROUND: The aim of this study was to investigate if epigenetically modified human mesenchymal stromal cells (hMSCs) can regulate the Th17-related immune responses. METHODS: We tested epigenetic drug combinations at various doses and selected the four combinations that resulted in maximal interleukin (IL)-10 and indoleamine 2,3-dioxygenase gene expression in hMSCs. We examined the effects of epigenetically modified hMSCs (epi-hMSCs) on CD4+ T-cell proliferation and inflammatory cytokine secretion under Th0- and Th17-polarizing conditions using mixed lymphocyte reactions and enzyme-linked immunosorbent assays (ELISAs). We determined Th17 cytokine levels and the percentage of Th17 cells among synovial fluid mononuclear cells (SFMCs) from rheumatoid arthritis (RA) patients by ELISA and flow cytometry. RESULTS: Epi-hMSCs inhibited the development of IL-17-producing cells in culture. The percentages of IL-17+ and interferon (IFN)-γ+ cells among peripheral blood mononuclear cells from healthy donors were lower under both the Th0 and Th17 conditions in the presence of epi-hMSCs than in the presence of no or untreated hMSCs. Epi-hMSC-treated RA patient SFMCs secreted lower levels of IL-17 and IFN-γ than RA patient SFMCs cultured without hMSCs or with untreated hMSCs. CONCLUSIONS: An optimal combination of hypomethylating agents and histone deacetylase inhibitors can enhance the immunomodulatory potential of hMSCs, which may be useful for RA treatment. PMID: 30092847 [PubMed - in process]
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Related Articles Intravenous Infusion of Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Rheumatoid Arthritis: A Phase Ia Clinical Trial. Stem Cells Transl Med. 2018 Sep;7(9):636-642 Authors: Park EH, Lim HS, Lee S, Roh K, Seo KW, Kang KS, Shin K Abstract Based on immunomodulatory actions of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs), in vitro or preclinical studies of hUCB-MSCs have been conducted extensively in rheumatoid arthritis (RA). However, few human trials have investigated the outcomes of hUCB-MSC infusions. The CURE-iv trial was a phase I, uncontrolled, open label trial for RA patients with moderate disease activity despite treatment with methotrexate. The patients received a single intravenous infusion of 2.5 × 107 , 5 × 107 , or 1 × 108 cells of hUCB-MSCs for 30 minutes, three patients in each cluster, with an increment of cell numbers when there was no dose-limited adverse event. Clinical and safety assessments were performed during the study period, and serum cytokines were measured at baseline and 24 hours after the infusion. Out of 11 screened RA patients, 9 were enrolled. The participants were predominantly female (78%) and the mean age was 57.4 years. The mean disease duration was 9.5 years, and baseline 28-joint disease activity score (DAS28; using erythrocyte sedimentation rate) was 4.53. There was no major toxicity in all clusters up to 4 weeks after the infusion. Serum erythrocyte sedimentation rate changes at 4 weeks (n = 9) were -7.9 ± 10.4 (p = .0517) and DAS28 changes were -1.60 ± 1.57 (p = .0159). Reduced levels of IL-1β, IL-6, IL-8, and TNF-α at 24 hours were observed in the cluster infused with 1 × 108 MSCs. This phase Ia hUCB-MSC infusion trial for established RA patients revealed no short-term safety concerns. Stem Cells Translational Medicine 2018. PMID: 30112846 [PubMed - in process]
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Related Articles Gene Delivery of Alpha-1-Antitrypsin Using Recombinant Adeno-Associated Virus (rAAV). Methods Mol Biol. 2018;1826:183-196 Authors: Song S, Lu Y Abstract The challenge for alpha-1-antitrypsin (AAT also known as SERPINA1) gene therapy is to achieve long term and high levels of AAT production. Recombinant adeno-associated virus (rAAV) vector has several advantages for AAT gene delivery including no viral genes in the vector, no requirement of integration for long-term transgene expression, low immunogenicity, and wide tropism. AAV-mediated AAT gene therapy has been developed and tested in animal models for AAT deficiency, type 1 diabetes, rheumatoid arthritis, and osteoporosis. AAV-mediated AAT gene therapy has also been tested in clinical studies and has shown promising results. Here we describe the methods of rAAV-AAT vector construction and production as well as AAT gene delivery through (1) liver-directed, (2) muscle-directed, and (3) mesenchymal stem cell (MSC)-mediated routes. We will also describe methods for the evaluation of AAT expression for each delivery approach. PMID: 30194601 [PubMed - in process]
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Related Articles Possibility of inhibiting arthritis and joint destruction by SSEA-3 positive cells derived from synovial tissue in rheumatoid arthritis. Regen Ther. 2017 Dec;7:82-88 Authors: Kurose R, Sawai T, Oishi K, Liu X, Sasaki A, Kurose A, Kumagai N, Fujishima Y, Ishibashi Y Abstract Aim: Joint destruction progresses irreversibly once they occur in rheumatoid arthritis (RA), even with the recent development of anti-rheumatic drugs. Cells positive for stage-specific embryonic antigen-3 (SSEA-3), a marker of human embryonic stem cell, act as stem cells in the blood. The aim of this study is to investigate the effectiveness of SSEA-3 positive cells for the treatment for RA. Methods: Synovial tissues were harvested at the time of joint surgery in RA patients. Cultured synovial cells were sorted by anti-SSEA-3 antibody using flow cytometry and were analyzed in in vitro. To investigate inhibitory effects on arthritis by SSEA-3 positive cells, collagen antibody-induced arthritis (CAIA) mice were used and transplanted with labeled cells intravenously. Results: Presence of SSEA-3 positive cells was confirmed with approximately 1% in RA synovial cells. SSEA-3 positive cells were negative for CD34 and positive for CD44, CD90 and CD105. Multipotency of SSEA-3 positive cells was higher than that of SSEA-3 negative cells. Arthritis of the group transplanted with SSEA-3 positive cells in CAIA mice decreased over time. Conclusions: SSEA-3 positive cells derived from RA synovial tissue might have the inhibitory effect on arthritis and would be one of cell source for new RA treatment. PMID: 30271856 [PubMed]
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Related Articles Comparative Molecular Characterization to Reveal Surface Behaviour of Non-proteolytic Bromelain Mutants. Curr Pharm Biotechnol. 2018 Oct 17;: Authors: Rajan GS, Sharma A, Kumari P, Biswas S Abstract Rheumatoid Arthritis (RA) is a chronic autoimmune disease that results in the systemic inflammation principally affecting the capsule covering the articulating ends of the synovial joints. Pharmacological treatment involving analgesics and anti-inflammatory drugs including steroids suppress the symptoms and have no effect on disease progression. However, disease modifying anti rheumatic drugs (DMARD) used for the treatment were still analysed for their long term effects. Bromelain has been widely used as phytotherapeutic drug owing to its anti-inflammatory, analgesic, anti-tumor and fibrinolytic properties. Bromelain refers to the combination of thiol proteases available in the extract of Ananas comosus. The fibrinolytic property confers to the reduced pannus development and hence the prevention of disease progression. It had been inferred that the observed clinical significance may not be solely accounted for its proteolytic property but also may be due to its hormone like behaviour (i.e.) non-canonical interactions to initiate the signal transduction pathway. The hormone like behaviour has been studied in cell models, suggesting that bromelain acts at system level. In the present study, molecular behaviour of the wild type and mutant proteins has been studied by simulating the predicted structure in an aqueous system. The comparative study of the mutants revealed that the mutant with both C26A and H158F mutations has the similar surface properties compared to the other mutants and can be used in studying the non-enzymatic interactions. Thus, this study may prove to be a tool in experimental studies to understand the hormone like behaviour and in construction of oral immunogenic synthetic peptides for treating inflamed conditions. PMID: 30332945 [PubMed - as supplied by publisher]
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Related Articles Сase Report of Acute Toxic Imatinib-induced Hepatitis in a Patient with Chronic Myeloid Leukemia, Sulfa Allergy, and Rheumatoid Arthritis. Cureus. 2018 Aug 13;10(8):e3136 Authors: Lopina N, Dyagil I, Hamov D, Zhuravlyova L, Dmytrenko I, Lopin D, Igor K Abstract The introduction of imatinib has substantially changed the approaches to the therapy of chronic myeloid leukemia. However, this drug can cause hepatic failure and death in rare cases. This report describes a clinical case of acute, toxic imatinib-induced hepatitis in a 56-year-old woman with chronic myeloid leukemia and concomitant sulfa allergy and rheumatoid arthritis. The patient developed acute imatinib-induced hepatitis after three months of treatment with imatinib and three days after increasing the imatinib dosage from 400 mg per day to 600 mg per day, resolving within three months after imatinib discontinuation and prednisolone administration. This confirms the necessity of great caution during imatinib therapy and the monitoring of liver tests. Approximately 25 reports about clinical cases of imatinib-induced hepatitis have been published up to the present. PMID: 30345193 [PubMed]
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Related Articles Therapeutic tolerance in autoimmune disease. Semin Arthritis Rheum. 2018 12;48(3):558-562 Authors: Rayner F, Isaacs JD Abstract Experimental immune tolerance induction, enabling tissues to be transplanted across animal strains, was first demonstrated in the 1950s. Therapeutic tolerance induction, whereby immune tolerance is used to treat or prevent transplant rejection, and as a treatment for autoimmunity, followed in the 1980s. Clinical translation has been slow but the pace of change is accelerating. Numerous strategies are now being tested clinically, ranging from monoclonal antibodies against T-cells, to peptide therapies, cellular therapies and microbiome manipulation. Furthermore, technology has advanced to the stage where we can start to monitor serological and cellular autoreactivity as biomarkers of response. In terms of autoimmunity, recognition of the prolonged phase of preclinical autoimmunity in several conditions, is leading to debate around treatment of at risk individuals, and trials in patients with prodromal clinical symptoms, such as seropositive arthralgia. Additionally, potent immunomodulatory drugs are achieving a substantial track record of safety. Putting these various factors together suggests that we can soon expect to see more trials of tolerogenic strategies in pre-clinical disease, with intensive immune monitoring to guide therapy. PMID: 30348449 [PubMed - in process]
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Related Articles Intra-articular treatment options for knee osteoarthritis. Nat Rev Rheumatol. 2018 Nov 29;: Authors: Jones IA, Togashi R, Wilson ML, Heckmann N, Vangsness CT Abstract Intra-articular drug delivery has a number of advantages over systemic administration; however, for the past 20 years, intra-articular treatment options for the management of knee osteoarthritis (OA) have been limited to analgesics, glucocorticoids, hyaluronic acid (HA) and a small number of unproven alternative therapies. Although HA and glucocorticoids can provide clinically meaningful benefits to an appreciable number of patients, emerging evidence indicates that the apparent effectiveness of these treatments is largely a result of other factors, including the placebo effect. Biologic drugs that target inflammatory processes are used to manage rheumatoid arthritis, but have not translated well into use in OA. A lack of high-level evidence and methodological limitations hinder our understanding of so-called 'stem' cell therapies and, although the off-label administration of intra-articular cell therapies (such as platelet-rich plasma and bone marrow aspirate concentrate) is common, high-quality clinical data are needed before these treatments can be recommended. A number of promising intra-articular treatments are currently in clinical development in the United States, including small-molecule and biologic therapies, devices and gene therapies. Although the prospect of new, non-surgical treatments for OA is exciting, the benefits of new treatments must be carefully weighed against their costs and potential risks. PMID: 30498258 [PubMed - as supplied by publisher]
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Related Articles Ankylosing spondylitis and mesenchymal stromal/stem cell therapy: a new therapeutic approach. Biomed Pharmacother. 2019 Jan;109:1196-1205 Authors: Abdolmohammadi K, Pakdel FD, Aghaei H, Assadiasl S, Fatahi Y, Rouzbahani NH, Rezaiemanesh A, Soleimani M, Tayebi L, Nicknam MH Abstract Ankylosing spondylitis (AS) is an inflammatory rheumatoid disease categorized within spondyloarthropathies (SpA) and manifested by chronic spinal arthritis. Several innate and adaptive immune cells and secreted-mediators have been indicated to play a role in AS pathogenesis. Considering the limitations of current therapeutic approaches (NSAIDs, glucocorticoids, DMARDs and biologic drugs), finding new treatments with fewer side effects and high therapeutic potentials are required in AS. Mesenchymal stem cells (MSCs) with considerable immunomodulatory and regenerative properties could be able to attenuate the inflammatory responses and help tissue repair by cell-to-cell contact and secretion of soluble factors. Moreover, MSCs do not express HLA-DR, which renders them a favorable therapeutic choice for transplantation in immune-mediated disorders. In the present review, we describe immunopathogenesis and current treatments restrictions of AS. Afterwards, immunomodulatory properties and applications of MSCs in immune-mediated disorders, as well as recent findings of clinical trials involving mesenchymal stem cell therapy (MSCT) in ankylosing spondylitis, will be discussed in detail. Additional studies are required to investigate several features of MSCT such as cell origin, dosage, administration route and, specifically, the most suitable stage of disease for ideal intervention. PMID: 30551369 [PubMed - in process]
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Related Articles Amelioration of clinical symptoms of patients with refractory rheumatoid arthritis following treatment with autologous bone marrow-derived mesenchymal stem cells: A successful clinical trial in Iran. Biomed Pharmacother. 2019 Jan;109:1834-1840 Authors: Ghoryani M, Shariati-Sarabi Z, Tavakkol-Afshari J, Ghasemi A, Poursamimi J, Mohammadi M Abstract Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune arthropathy characterized by synovial hyperplasia leading to functional impairment. Although the exact cause of RA is unknown, there is evidence suggesting the role of T cell subtypes in the pathogenesis of RA. Conventional therapy in some RA patients is associated with mild or severe side effects, and resistance of some patients has been reported to these types of therapy. The therapeutic potential of mesenchymal stem cells (MSCs) introduced them as a novel therapeutic choice for the treatment of rheumatic diseases. The aim of our study was to evaluate the effects of intravenous administration of autologous bone marrow-derived MSCs on the immunological, clinical and para-clinical factors such as regulatory T cells, Th17 cells, CD8+ T cells, CD4+ T cells, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), visual analogue scale (VAS), ESR, C-reactive protein (CRP), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP) antibodies in patients with refractory RA. Nine refractory RA patients with no other rheumatologic disorders were included in this study. All patients received a single intravenous dose of 1 × 106 autologous bone marrow-derived MSCs/kg, and were followed up at 1, 6 and 12 months after injection of MSCs. We found a significant decreasing trend in Th17 percentage and geometric mean fluorescence intensity for IL-17A following injection of MSCs at 12 months compared to the time point zero. Furthermore, a significant increase in regulatory T cells percentage was observed at the end of the first month after the intervention. DAS28-ESR decreased significantly at 1 and 12 months after MSC therapy. VAS score showed a significant decreasing trend during the follow-up periods. No significant difference was found for serum CRP and anti-CCP levels after the intervention. In conclusion, our data indicated that clinical symptoms were significantly ameliorated following the intravenous injection of autologous bone marrow-derived MSCs to the patients with refractory RA. PMID: 30551438 [PubMed - in process]
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Related Articles KIT as a therapeutic target for non-oncological diseases. Pharmacol Ther. 2018 Dec 14;: Authors: Martinez-Anton A, Gras D, Bourdin A, Dubreuil P, Chanez P Abstract KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed. PMID: 30557630 [PubMed - as supplied by publisher]
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Related Articles Recapitulation of methotrexate hepatotoxicity with induced pluripotent stem cell-derived hepatocytes from patients with rheumatoid arthritis. Stem Cell Res Ther. 2018 Dec 29;9(1):357 Authors: Kim J, Kim Y, Choi J, Jung H, Lee K, Kang J, Park N, Rim YA, Nam Y, Ju JH Abstract BACKGROUND: Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis (RA). The drug is cost-effective, but sometimes causes hepatotoxicity, requiring a physician's attention. In this study, we simulated hepatotoxicity by treating hepatocytes derived from RA patient-derived induced pluripotent stem cells (RA-iPSCs) with MTX. METHODS: RA-iPSCs and healthy control iPSCs (HC-iPSCs) were established successfully. RA-iPSCs were differentiated into hepatocytes in two-dimensional (2D) monolayers and three-dimensional (3D) hepatocyte spheroid cultures; this process required growth factors such as BMP4, bFGF, HGF, and OSM. Immunofluorescence staining and flow cytometry were performed to confirm that the mature hepatocytes expressed cytokeratin 18, anti-alpha-1 antitrypsin, and albumin. MTX toxicity was evaluated via monitoring of cell viability, alanine aminotransferase, and mitochondrial status after MTX treatment in 2D and 3D cultures. RESULTS: RA-iPSCs generated from three RA patients suffering from MTX-induced hepatotoxicity differentiated into the endoderm lineage, hepatoblasts, and hepatocytes. In 2D culture, RA-iPSC-derived hepatocytes were more sensitive to MTX than healthy controls. A 3D culture system using hepatocyte spheroids also successfully recapitulated MTX-induced hepatotoxicity. The 3D culture system had several advantages, including longer culture periods under more complex conditions. CONCLUSIONS: A patient-derived iPSC platform could recapitulate MTX toxicity. Simulation of drug toxicity in vitro may help clinicians choose safer drugs or less toxic doses. PMID: 30594247 [PubMed - in process]
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