Treatment of experimental arthritis by inducing immune tolerance with human adipose‐derived mesenchymal stem cells

Abstract

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 ADMSCs also induced de novo generation of antigenspecific 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.

Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

“…Murine bone marrow MSCs have shown contradictory results in reducing the disease severity in CIA model, despite inhibiting T cell proliferation in response to CII (34)(35)(36)(37). However, mouse and human ASCs have been reported to ameliorate CIA by modulating T cell responses (15,38). It appears that MSCs from adipose tissue could be advantageous over those from bone marrow for the treatment of arthritis, although it needs to be supported by more experimental evidences.…”

“…Despite several conflicting reports, MSCs from various tissues have shown protective effect in reducing autoimmune and inflammatory processes in preclinical models of RA (13)(14)(15). However, the role of MSCs in protecting skeletal component of arthritis, including pathological bone loss and the bone-resorbing osteoclasts, has not been well studied.…”

Pre-treatment with IL-1β enhances the efficacy of MSC transplantation in DSS-induced colitis

“…1,2 MSC-based therapies have provided convincing evidence for their potential antiinflammatory and immunomodulatory effects in treating a variety of inflammatory and autoimmune diseases, including ulcerative colitis (UC), 3 rheumatoid arthritis 4 and sepsis. 5 MSCs can migrate to sites of tissue damage, 6,7 where they are activated by inflammatory cytokines (such as IFN-c) and several chemokines, which can recruit or suppress lymphocytes.…”

Update on biological therapies for knee injuries: osteoarthritis

“…Systemic delivery of stem cells also has been studied [31]. A systemic infusion of adipose MSCs showed a reduction in OA incidence and severity in an animal model (mice).…”

“…A systemic infusion of adipose MSCs showed a reduction in OA incidence and severity in an animal model (mice). The success of the therapeutic effect was achieved by reducing the expansion of antigen-specific cellular Th1/Th17, decreasing the production of several inflammatory cytokines and chemokines, inducing the production of IL-10 from local lymph nodes, and stimulating the production of CD4 + T lymphocytes and other cell responses [31]. The concept of systemic use of stem cells is interesting because it addresses all peri-articular tissues, including subchondral bone and muscles.…”