Objective: Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a model for human Scl-cGVHD and systemic sclerosis (SSc). Sphingosine-1-phosphate (S1P) exerts a variety of activities in immune response, inflammation, and vascular systems. It was reported that regulation of S1P on fibrotic diseases as well as systemic sclerosis. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and the treatment of autoimmune diseases. In this study, the effects of FTY720 were investigated in Scl-cGVHD. Methods: FTY720 was orally administered to allogeneic recipients from day 0 to day 20 (short-term, early-treatment group), day 0 to day 42 (full-term, early-treatment group), or day 22 to day 42 (delayed-treatment group) after bone marrow transplantation (BMT). Results: Delayed-treatment of FTY720 attenuated and early-treatment inhibited Scl-cGVHD severity and fibrosis. In early-treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, regulatory T cells and regulatory B cells. Vascular damages in Scl-cGVHD were inhibited by FTY720 through downregulating serum levels of S1P and sE-Selectin. Furthermore, FTY720 inhibited the infiltration of immune cells into the skin and diminished the expression of mRNA for proinflammatory cytokines in the skin. Conclusion: These results suggest that FTY720 could be a promising strategy for treating Scl-cGVHD and SSc patients.
- Copyright © 2013 by The American Association of Immunologists, Inc.