LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation

Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transpl antation (BMT). Recent studies have demonstrated that the loss of gastroint estinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulati on that contributes to GVHD. Using a mouse BMT model, we studied the effect s of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-alpha levels, decreased intestinal histopathol ogy, and resulted in significantly improved survival and a reduction in cli nical. GVHD, compared with control-treated animals. Importantly, B975 had n o effect on donor T cell responses to host antigens in vivo or in vitro. Wh en mice received lethal doses of P815 tumor cells at the time of BMT, admin istration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.