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.