Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect.

Abstract

Acute graft-versus-host disease (GvHD) causes significant mortality in patients undergoing allogeneic hematopoietic cell transplantation. Immunosuppressive treatment for GvHD can impair the beneficial graft-versus-leukemia effect and facilitate malignancy relapse. Therefore, novel approaches that protect and regenerate injured tissues without impeding the donor immune system are needed. Bile acids regulate multiple cellular processes and are in close contact with the intestinal epithelium, a major target of acute GvHD. Here, we found that the bile acid pool is reduced following GvHD induction in a preclinical model. We evaluated the efficacy of bile acids to protect the intestinal epithelium without reducing anti-tumor immunity. We observed that application of bile acids decreased cytokine-induced cell death in intestinal organoids and cell lines. Systemic prophylactic administration of tauroursodeoxycholic acid (TUDCA), the most potent compound in our in vitro studies, reduced GvHD severity in three different murine transplantation models. This effect was mediated by decreased activity of the antigen presentation machinery and subsequent prevention of apoptosis of the intestinal epithelium. Moreover, bile acid administration did not alter the bacterial composition in the intestine suggesting that its effects are cell-specific and independent of the microbiome. Treatment of human and murine leukemic cell lines with TUDCA did not interfere with the expression of antigen presentation-related molecules. Systemic T-cell expansion and especially their cytotoxic capacity against leukemic cells remained intact. This study establishes a role for bile acids in the prevention of acute GvHD without impairing the graft-versus-leukemia effect. In particular, we provide a scientific rationale for the systematic use of TUDCA in patients undergoing allogeneic hematopoietic cell transplantation.