BI-5756 Reduces Graft-Versus-Host Disease Through CB1-Mediated Treg Upregulation

Cannabinoid Receptor 1 (CB1) has been implicated in multiple inflammatory diseases by regulating pro-inflammatory mediators or altering immune cell polarization. However, the expression and direct functional role of CB1 in T cells remain largely unexplored. Here, we demonstrate that primary murine T cells express CB1 and that its novel agonist, BI-5756, directly increases the frequencies of regulatory T cells (Tregs) in primary murine pan T cells after activation. In addition, BI-5756 exhibits an in vivo protective effect against graft-versus-host disease (GvHD), an allogeneic T cell-mediated inflammatory complication after allogeneic hematopoietic cell transplantation (allo-HCT), resulting in an improved overall survival with enhanced platelet recovery and reconstitution of bone marrow-derived B and T cells. BI-5756 also directly suppresses tumor cell growth and upregulates MHC I, MHC II, and CD80 on tumor cells, which may subsequently enhance T cell-mediated anti-tumor responses in mixed lymphocyte reaction with A20 cells. The ability of BI-5756 to increase Tregs was significantly abrogated by rimonabant, a potent and selective CB1 Antagonist, suggesting that the immunomodulatory effect of BI-5756 is mediated via CB1. In summary, BI-5756, a potent CB1 Agonist, increases Tregs while preserving anti-tumor responses in vitro and effectively reduces GvHD in vivo.

cannabinoid receptor1; graft-versus-host disease; regulatory T cells.