Allogeneic hematopoietic stem cell transplantation (allo-HSCT) following 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 a 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. Here, using GVHD model allo-HSCT, we further investigated the effect of DZNep on allogeneic T cell response and the hematopoietic chimerism in recipients. We found that DZNep could delay the in vivo proliferation of donor-derived alloreactive CD8⁺ T cells, and also reduced the IL-2 production by these T cells. Moreover, DZNep treatment resulted in a significant decrease of IFN-Γ, TNF-Α, granzyme B, Trail and Fas ligand expressing donor-derived CD8⁺ T cells, suggesting a multi-level modulation role on T cell survival and effect in vivo. Notably, DZNep treatment did not hamper the generation of hematopoietic chimerism in recipients. These findings suggest that modulation of histone methylation through DZNep may be a potential strategy for the hematopoietic chimerism induction so as to achieve donor-specific organ allograft tolerance through donor allo-HSCT following solid-organ transplantation.

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