PD-1H/VISTA Agonism Inhibits Host Myeloid Antigen Presenting Cells That Suppresses Acute Graft-Versus-Host Disease without Losing Graft-Versus-Leukemia Effect

Programmed Death-1 Homolog (PD-1H, also known as VISTA) is an inhibitory molecule of the immunoglobulin superfamily and broadly found in hematopoietic cells. Acute GVHD (aGVHD) occurs when donor T cells are primed and activated by host antigen-presenting cells (APCs). We previously demonstrated that PD-1H agonists prevent aGVHD in murine MHC mismatched bone marrow transplantation (BMT) models. Interestingly, the treatment of PD-1H agonists (clone: MH5A) on day 0 of BMT was capable of fully preventing GVHD, while treatment of PD-1H agonists at different timepoints (day -3, +3, +7 of BMT) did not prevent aGVHD in MHC mismatched BMT models. In addition, we transplanted wildtype (WT) C57B/L6 (B6) bone marrow cells (BM) and T cells into either PD-1H knock-out (KO) or WT BALB/c mice as hosts following lethal irradiation. PD-1H KO host mice developed more severe aGVHD and conferred worse survival when compared to WT host mice. To test which cell subsets expressing PD-1H in host mice regulate aGVHD, we transplanted WT BALB/c BM and T cells into B6 myeloid lineage specific (LysM-Cre) or neutrophil (Ly6G-Cre) specific PD-1H KO or WT host mice. Interestingly, the myeloid or neutrophil lineage specific KO host mice had worse aGVHD symptoms and conferred worse survival compared with WT littermates. Our studies indicate that PD-1H expression on host myeloid APCs regulates aGVHD. These data suggest that the PD-1H agonists may inhibit ‘host APCs’ during donor T cell priming phase, leading to suppression of GVHD. To test this, we transplanted B6 PD-1H KO BM and T cells into BALB/c WT host mice and treated either host mice with or without PD-1H agonists. Consistent with prior data, host mice treated with PD-1H agonists delayed aGVHD symptoms and extended survival compared with isotype control treated mice. Ex vivo allogenic mixed lymphocyte reaction experiments demonstrated that allogeneic T cell proliferation was higher in co-culture with PD-1H KO myeloid APCs than WT myeloid APCs; allogeneic T cell proliferation in co-culture with WT myeloid APCs was inhibited in the presence of PD-1H agonists compared with isotype controls. These data support PD-1H agonist-mediated suppression of host myeloid APCs leading to inhibition of aGVHD. In addition, we found that PD-1H agonist treatment increased inhibitory myeloid cells including myeloid-derived suppressor cells (MDSCs), N2 neutrophils and M2 macrophages in host GVHD mice. To determine whether PD-1H agonists do not interfere graft-versus-leukemia (GVL) effects, we assessed in vivo leukemia (A20) proliferation in in MHC mismatched BMT models following PD-1H agonist treatment. Despite the treatment of PD-1H agonists, in vivo leukemia proliferation remained to be inhibited while GVHD was suppressed. Altogether, new mechanisms of PD-1H agonism on inhibiting aGVHD enable to develop logical therapeutic approaches for aGVHD treatment, such as myeloid APC suppression.