PD-1 blockade later but not at post-transplant attenuates chronic graft-versus-host disease

Abstract

Abstract PD-1 and its ligand PD-L1 are widely appreciated as targets of immune checkpoint blockade. We sought to investigate the role of the PD-1 pathway in the context of chronic graft-versus-host disease (cGVHD). To induce cGVHD, mice are conditioned with Cytoxan and radiation prior to MHC disparate bone marrow (BM) + T cells (70k) and develop multi-organ symptoms with bronchiolitis obliterans lung manifestations. CGHVD mice have high survival rates past 50 days, with <15% weight loss over this period. Anti-PD-1 mAb given to mice with established cGVHD resulted in disease attenuation assessed by significantly improved pulmonary function tests compared to irrelevant mAb controls. PD-1 blockade significantly reduced germinal center (GC)-promoting GC B and T follicular helper (Tfh) cell and increased GC-suppressing T-follicular regulatory (Tfr) cell frequencies. However, in studies with mice given five percent higher T cell dose, resulting in T cell rather than GC-mediated disease, anti-PD-1 mAb dramatically worsened cGVHD severity. To assess GC cell-specific effects, recipients were given PD-1-deficient cells in graft compartments. Mice receiving PD-1 KO T cells predictably exhibited marked escalation of cGVHD severity and lethality, while mice receiving PD-1 KO B cells showed diminished disease, with significant improvement in pulmonary function. Co-culture of isolated B, Tfh and Tfr cells from NP-OVA immunized mice to determine effects of individual GC cell populations on Ig class switching demonstrated significant increase in Tfr suppressive capacity with addition of anti-PD-1 mAb. Together, these data provide evidence for PD-1 support of the GC reaction and identifies the PD-1/PD-L1 axis as a potential target for cGVHD therapy.