Modulation of Allogeneic CD8+ T-Cell Response by DZNep Controls GVHD While Preserving Hematopoietic Chimerism

BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with solid-organ transplantation is a feasible method to achieve long-lasting organ allograft tolerance through the induction of hematopoietic chimerism in recipients. However, the allo-HSCT engraftment puts recipients at risk of life-threatening graft-versus-host disease (GVHD). Novel immunomodulatory approaches are required to effectively control GVHD while preserving the status of hematopoietic chimerism. We have reported that histone methylation inhibitor 3-deazaneplanocin A (DZNep) can control ongoing GVHD in mice by selectively inducing apoptosis of alloreactive effector T cells. METHODS Using donor-derived CD8 T cell-mediated mouse GVHD model, we further investigated the effect of in vivo administration of DZNep on allogeneic CD8 T cell response and the hematopoietic chimerism in recipients. RESULTS We found that DZNep delayed the in vivo proliferation of donor-derived alloreactive CD8 T cells and also reduced the interleukin-2 production by these T cells. Moreover, DZNep treatment resulted in a significant decrease of interferon-γ, tumor necrosis factor-α, granzyme B, TRAIL, and Fas ligand expressing donor-derived CD8 T cells, suggesting a multilevel modulation role on T-cell survival and effect in vivo. Notably, DZNep treatment did not hamper the generation of hematopoietic chimerism in recipients. CONCLUSIONS These findings suggest that modulation of histone methylation through DZNep may be a potential strategy for the induction of hematopoietic chimerism to achieve donor-specific organ allograft tolerance through donor allo-HSCT combined with solid-organ transplantation.