LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation
Kenneth R. Cooke, Armin Gerbitz, James M. Crawford, Takanori Teshima, Geoffrey R. Hill, Amy Tesolin, Daniel P. Rossignol, James L.M. Ferrara
Kenneth R. Cooke, Armin Gerbitz, James M. Crawford, Takanori Teshima, Geoffrey R. Hill, Amy Tesolin, Daniel P. Rossignol, James L.M. Ferrara
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LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation

Abstract

Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects 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-α levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration 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.

Authors

Kenneth R. Cooke, Armin Gerbitz, James M. Crawford, Takanori Teshima, Geoffrey R. Hill, Amy Tesolin, Daniel P. Rossignol, James L.M. Ferrara

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Treatment with B975 results in decreased intestinal histopathology after...
Treatment with B975 results in decreased intestinal histopathology after allogeneic BMT. B6D2F1 animals received syngeneic BMT or allogeneic BMT from C57BL/6 donors as in Figure 1. On days +4 to +6, small-bowel samples from BMT recipient mice were obtained and analyzed microscopically as described in Methods. Syngeneic BMT recipients (a) demonstrate reestablishment of intestinal architecture with villi of near normal length and without significant cellular infiltration into the lamina propria. Regenerative change is evident by focally increased nuclear staining and an increased nuclear/cytoplasmic ratios. Animals treated with B975 (b) exhibit partial restoration of small-intestinal villous architecture, regenerative change, and little inflammatory infiltration. Recipients of allogeneic BMT (c) show severe intestinal toxicity including surface erosion, villous blunting, epithelial attenuation, and an intense cellular infiltration in the lamina propria. Original magnification, ×200.