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.

TNF Enhances CD4+ T Cell Alloproliferation, IFN-γ Responses, and Intestinal Graft-Versus-Host Disease by IL-12-Independent Mechanisms

“…Previous investigators have suggested that the mechanism of the actions of TNF during acute GVHD was as an effector of host cytotoxicity (9,43). More recent studies have demonstrated that the absence of TNFR1 on host cells was associated with a delay in mortality from acute GVHD, but had no effect on histologic patterns of GVHD in the intestinal tract or liver (42).…”

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls and a known agonist of Toll-like receptor 4 (TLR-4) (24), is considered a major marker of microbial translocation (25)(26)(27). In addition to local defense against microbial translocation at the level of the GI mucosa and within the liver, several lines of protection are active in the systemic circulation to neutralize translocating LPS and its downstream effects as a potent immune-activating molecule, thus limiting the detrimental effects of microbial translocation.…”

Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

“…During the early phase of GvHD LPS is a major pathogenic factor that enhances GvHD and leads to the activation of DCs. 37 Therefore, we evaluated the effects of Syk signaling in unstimulated and LPS-stimulated DCs. LPS enhanced expression of the costimulatory molecules CD80, CD86, CD40 and major histocompatibility complex class I and II.…”