The protection and therapy effects of bortezomib in murine acute graft-versus-host disease

Acute graft-versus-host disease (aGVHD) remains a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The proteasome inhibitor bortezomib exhibits potent antitumor activity with anti-inflammatory and immunomodulatory effects. However, the effects of bortezomib on aGVHD are unclear. In this study, we assessed the effects of bortezomib on aGVHD in the C57BL/6 (H-2b+) donor to BALB/c (H-2d+) recipient major histocompatibility complex-mismatched model. Two bortezomib doses (1 mg/kg each) on days 0 and +1 after transplantation, significantly increased survival rate and attenuated clinical signs of aGVHD without altering donor reconstitution. However, GVHD-associated mortality was significantly increased when bortezomib administration was delayed to day +2 posttransplantation. Furthermore, a single dose of bortezomib on day 0 or day +1 after transplantation also decreased the GVHD protective effect. Consistent with the above data, serum cytokine levels of IL-2, IFN-γ and TNF-α were significantly decreased at day +7 posttransplantation after two doses of bortezomib compared with aGVHD control group. Moreover, two administrations of bortezomib reduced donor T-cell expansion at days +3 and +4 posttransplantation and enhanced donor CD4(+)T-cell differentiation into the T help cell 17 subset at day +7 after transplantation in spleens. These results indicated that the protective effects of bortezomib on aGVHD were dependent on the time and the frequency of bortezomib administration.