Effects of decitabine on allogeneic immune reactions of donor lymphocyte infusion via activation of dendritic cells

Background: Successful prevention of post-transplantation relapse after donor lymphocyte infusion (DLI) depends on its capability to mediate an effective graft-versus-leukemia (GVL) response while minimizing DLI-related toxicity, including graft-versus-host disease (GVHD). Methods: We assessed the effects of decitabine (DEC), a hypomethylating agent, upon allogeneic immune reaction in a murine model of DLI. Results: Significantly greater tumor growth retardation and survival prolongation occurred in mice administered with 1.0 mg/kg DEC for 5 days (DEC-1.0) than in control or DEC-0.1 mice. Upon prompt DEC and DLI co-administration, dendritic cells (DCs) were activated; DEC-1.0/DLI induced severe GVHD, and survival was significantly lower than with DLI alone or DEC-0.1/DLI treatments. IFN-γand CD28 levels were higher in splenic DCs of DEC-1.0 mice than in those of control mice. Assessment of delayed DLI co-administration with DEC, when IFN-γlevels were normalized to control levels, revealed that DEC-1.0/DLI successfully facilitated tumor management without causing severe GVHD. Conclusions: Our results suggest that DEC primes allogeneic immune reactions of DLI via DC activation, and GVHD and GVL effects are separable through optimal DLI timing based on DEC-induced increase in IFN-γexpression levels.