Background and aims: Inflammatory bowel diseases (IBDs) are associated with uncontrolled innate and adaptive immunity against normal constituents, including commensal bacteria and microbial products. Mesenchymal stem cells (MSCs) suppress effector T cell responses and have beneficial effects in various immune disorders. This work investigates the therapeutic effects of human adipose-derived MSCs (hASCs) in various models of IBD and sepsis. Methods: Acute and chronic colitis was induced in mice with dextran sulfate sodium. Sepsis was induced by caecal ligation and puncture or by endotoxin injection. Colitic and septic mice were treated intraperitoneally with hASCs or murine ASCs, and diverse disease clinical signs and mortality were determined. The levels of various inflammatory cytokines and chemokines, T helper 1(Th1)-type response and generation of regulatory T cells (Treg) were determined in affected organs. Results: Systemic infusion of ASCs significantly ameliorated the clinical and histopathological severity of colitis, abrogating weight loss, diarrhoea and inflammation, and increasing survival. The therapeutic effect was associated with downregulation of the Th1-driven inflammatory responses. ASCs decreased a wide panel of inflammatory cytokines and chemokines and increased interleuklin 10 (IL10), acting on macrophages. hASCs also impaired Th1 cell activation in both colonic mucosa and draining lymph nodes. The induction of IL10-secreting Treg was partially involved in the therapeutic effect of hASCs. Moreover, ASCs protected from severe sepsis by reducing the infiltration of inflammatory cells in various target organs and by downregulating the production of various inflammatory mediators. Conclusions: hASCs emerge as key regulators of immune/inflammatory responses in vivo and as attractive candidates for cell-based treatments for IBD and sepsis.

Objective: Rheumatoid arthritis (RA) is a chronic autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Adult mesenchymal stem cells (MSCs) were recently found to suppress effector T cell responses and to have beneficial effects in various immune disorders. The purpose of this study was to examine a new therapeutic strategy for RA based on the administration of human adipose‐derived MSCs (AD‐MSCs).Methods: DBA/1 mice with collagen‐induced arthritis were treated with human AD‐MSCs after disease onset, and clinical scores were determined. Inflammatory response was determined by measuring the levels of different mediators of inflammation in the joints and serum. The Th1‐mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen. The number of Treg cells and the suppressive capacity on self‐reactive Th1 cells were also determined.Results: Systemic infusion of human AD‐MSCs significantly reduced the incidence and severity of experimental arthritis. This therapeutic effect was mediated by down‐regulating the 2 deleterious disease components: the Th1‐driven autoimmune and inflammatory responses. Human AD‐MSCs decreased the production of various inflammatory cytokines and chemokines, decreased antigen‐specific Th1/Th17 cell expansion, and induced the production of antiinflammatory interleukin‐10 in lymph nodes and joints. Human AD‐MSCs also induced de novo generation of antigen‐specific CD4+CD25+FoxP3+ Treg cells with the capacity to suppress self‐reactive T effector responses.Conclusion: Human AD‐MSCs emerge as key regulators of immune tolerance by inducing the generation/activation of Treg cells and are thus attractive candidates for a cell‐based therapy for RA.

Objectives: Adult mesenchymal stem cells were recently found to suppress effector T cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autoreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterise the immunosuppressive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from patients with RA. Methods: The effects of hASCs on collagen-reactive RA human T cell proliferation and cytokine production were investigated, as well as effects on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from patients with RA. Results: hASCs suppressed the antigen-specific response of T cells from patients with RA. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the numbers of IL10-producing T cells and monocytes were significantly augmented upon hASC treatment. The suppressive activity of hASCs was cell-to-cell contact dependent and independent. hASCs also stimulated the generation of FoxP3 protein-expressing CD4⁺CD25⁺ regulatory T cells, with the capacity to suppress collagen-specific T cell responses. Finally, hASCs downregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from patients with RA. Conclusions: The present work identifies hASCs as key regulators of immune tolerance, with the capacity to suppress T cell and inflammatory responses and to induce the generation/activation of antigen-specific regulatory T cells.