B7-H1 agonists could prevent disseminated inflammation by desensitizing cell susceptibility to cytotoxic T-cells.

The B7-H1/PD-1 immune co-inhibitory pathway is functionally bi-directional. We showed previously that B7-H1 could be widely induced on various types of cells and, in addition to be a ligand for PD-1 on T-cells, also serve as an anti-apoptotic receptor upon interacting with PD-1. We explored the role of B7-H1 as a receptor in protecting allogeneic T-cell mediated host cell destruction and systemic inflammation using mouse models of graft-versus-host disease (GVHD). Administer of by PD-1Ig or a B7-H1 monoclonal antibody (mAb) led to accelerated progression and rapid death in mice transferred with wild type allogeneic T-cells, supporting a dominant role of this pathway in the suppression of allogeneic T-cell response. In sharp contrast, PD-1Ig or B7-H1 mAb could behave as the B7-H1 agonists and drastically ameliorate the progression of GVHD and induced long-term tolerance in the context of transferring PD-1 deficient allogeneic T-cells. We further demonstrated that B7-H1 agonists decreased susceptibility of normal hematopoietic cells to allogenic T-cell lysis in vitro and in vivo. More importantly, mice that developed tolerance could still mount graft-versus-leukemia response. Our findings indicate a role for intrinsic B7-H1 in protecting host cells during systemic inflammation and have implications for treating human diseases including GVHD.