| Objectives:Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder, mainly characterized by synovial inflammation and hyperplasia, cartilage/bone damage, and systemic comorbidities. The pathological process is persistent and recurrent, resulting in high morbidity. This is a common disease which can be found at any age in all races. The potential pathogenic mechanisms that initiate and lead to the development of RA include gene-environment interactions, synovial immunologic processes and inflammation, and a loss of immunological self-tolerance. Therefore, anti-inflammation and restore the loss of immunological self-tolerance are two key points for the treatment of RA. The applications of traditional drugs and recent biological treatments are limited because of the obvious side effects and lack of ability to repair the joint damage and immune system. With the development of tissue engineering and gene engineering, stem cell has become a new therapeutic method for RA patients. The dual-function of anti-inflammation and mediate the immune system from mesenchymal stem cells (MSCs) makes MSCs a new prospect for RA treatment. This study was designed to assess the safety and efficacy and explore the mechanisms of human umbilical cord MSCs (hUC-MSCs) in treatment of RA.Methods:137active RA patients without adequate responses to traditional medication were enrolled and treated by4×107hUC-MSCs/person/cycle for2-3cycles. The treatment-related adverse events and the clinical information were recorded. Tests for serological markers to assess safety and disease activity were conducted at different time points. Serum levels of inflammatory chemokines/cytokines were measured and lymphocyte subsets in peripheral blood were analyzed.To further study the mechanism, we use Foxnl-/-mice which have dysplastic thymus as the animal model. After hUC-MSCs treatment, we analyzed the restoration of the Foxn1-/-thymus rudiment and the thymopoiesis of naive T cells and regulatory T cells (Tregs) on newly developed thymus rudiment.Results:None of the patients were found to have serious adverse effects during or after infusion. The serum levels of tumor necrosis factor-alpha (TNF-a) and interleukin-6(IL-6) significantly decreased post-first treatment (p<0.05), in the meantime, the percentage of CD4+CD25+Foxp3+Tregs in the peripheral blood significantly increased compared with control group (p<0.05). The treatment induced a significant remission of disease according to the American College of Rheumatology (ACR) improvement criteria, the28-joint disease activity score (DAS28), and the Health Assessment Questionnaire (HAQ). The therapeutic effects can maintain for3-6months without continuous administration, and repeated infusion after this period can enhance the therapeutic efficacy, which was strongly correlated with the increased percentage of Tregs in peripheral blood.In animal study, the data showed well-organized cortex-medulla architecture and an obvious improvement in the maturation of thymus epithelial cells (TECs) along with the UEA-1+MHCⅡhi TECs appearing in the rudiment. We further demonstrated the improved thymopoiesis and the enhanced export of mature T cells with increased Tres in peripheral blood. Furthermore, we found that MSCs can engraft in the thymus’s tissue and express many cytokines, especially Keratinocyte Growth Factor (KGF), which was essential for the thymus development.Conclusions:Data from the current cohort indicated that hUC-MSCs infusion can provide safe, significant and persistent clinical benefits for RA patients probably through dual-function of anti-inflammation and immunoregulation. Data from the animal experiment suggested a new mechanism of hUC-MSCs which could provide a proper microenvironment for the reconstitution and functional maturation of thymus in Foxnl-/-mice, and elicited another insight in terms of therapeutical efficacy of MSCs in autoimmune diseases. |
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