Transforming Growth Factor β-Transduced Mesenchymal Stem Cells Ameliorate Experimental Autoimmune Arthritis Through Reciprocal Regulation of Treg/Th17 Cells and Osteoclastogenesis

Objective. Bone marrow-derived mesenchymal stem cells (MSCs) can prevent various autoimmune diseases. We examined the therapeutic potential of transforming growth factor beta (TGF beta)-transduced MSCs in experimental autoimmune arthritis, using an accepted animal model of collagen-induced arthritis (CIA). Methods. DBA/1.J mice with CIA were treated with syngeneic TGF beta-induced MSCs, whereas control mice received either vehicle or MSCs alone. Arthritis severity was assessed by clinical and histologic scoring. TGF beta-transduced MSCs were tested for their immunosuppressive ability and differential regulation in mice with CIA. T cell responses to type II collagen were evaluated by determining proliferative capacity and cytokine levels. The effects of TGF beta-transduced MSCs on osteoclast formation were analyzed in vitro and in vivo. Results. Systemic infusion of syngeneic TGF beta-transduced MSCs prevented arthritis development and reduced bone erosion and cartilage destruction. Treatment with TGF beta-transduced MSCs potently suppressed type II collagen-specific T cell proliferation and down-regulated proinflammatory cytokine production. These therapeutic effects were associated with an increase in type II collagen-specific CD4+FoxP3+ Treg cells and inhibition of Th17 cell formation in the peritoneal cavity and spleen. Furthermore, TGF beta-transduced MSCs inhibited osteoclast differentiation. Conclusion. TGF beta-transduced MSCs suppressed the development of autoimmune arthritis and joint inflammation. These data suggest that enhancing the immunomodulatory activity of MSCs and modulating T cell-mediated immunity using gene-modified MSCs may be a gateway for new therapeutic approaches to clinical rheumatoid arthritis.