The Nrf2 activator dimethyl fumarate inhibits acute graft-versus-host disease with retention of graft-versus-tumor effects

Abstract

Abstract Dimethyl fumarate (DMF), an activator of Nrf2, has been shown to have anti-inflammatory and immunomodulatory properties without significant immunosuppression. we therefore hypothesized that DMF could be a new candidate drug for the treatment of aGVHD with retention of GVT effect. Lethally irradiated BALB/c mice transplanted with B6 bone marrow plus splenocytes were administered DMF or vehicle solution by gavage daily from day -3 to day 3. DMF treatment inhibited aGVHD, accompanied by less weight loss and lower clinical score. DMF is capable of significantly inhibiting proliferation of alloreactive T cells in a dose-dependent manner in mixed lymphocyte reaction assay. Furthermore, the percentages of CD69+T cells and IFN-γ expressing T cells, were significantly increased in aGVHD target organs from DMF recipients. In addition, DMF treatment markedly increased the frequencies of Treg cells in target organs. Depletion of CD25+ cells in DMF recipients aggravated aGVHD mortality compared with IgG control recipients. Moreover, Treg polarizing assay suggested that DMF could promote Treg cell differentiation in vitro in a dose-dependent manner. In addition, No protective effects of DMF were observed in mice transplanted with BM and challenged with leukemia cells. However, DMF treatment significantly prolonged the survival in tumor-bearing mice that received an allogeneic BMT with donor splenocytes. we also observed that donor T cells recovered from DMF-treated recipients and controls showed comparable cytolytic activity against leukemia cells. In conclusion, our findings demonstrated that activation of Nrf2 with DMF may be of significant use in preventing aGVHD and preserving GVT responses.