Hsp90 inhibition ameliorates CD4 + T cell-mediated acute Graft versus Host disease in mice

摘要

Abstract Introduction For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co-transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)?￠????a potentially life-threatening complication. Methods Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. Results Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4 + T cell transplantation with the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia-bearing mice after transplantation of allogeneic CD4 + and CD8 + T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4 + T cells with a relative resistance of CD4 + regulatory and CD8 + T cells toward Hsp90 inhibition. Conclusions Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.