Agonistic anti-PD-1 antibodies downregulate autoantibody development in lupus model mice

Abstract T follicular helper (Tfh) cells provide B cell help and promote antibody development. Since Tfh cells may be responsible for the development of self-reactive antibodies, this CD4+ T cell subset represent a potential target in the treatment of autoimmune diseases. We have developed anti-PD-1 agonist antibodies that can stimulate the immunosuppressive activity of PD-1. In this study, we sought to inhibit Tfh cells that express PD-1 at high levels and to downregulate antibody production using the PD-1 agonists. PD-1 agonist antibody suppressed IL-21 production from human Tfh-like cells. The co-treatment with PD-1 agonist antibody significantly reduced antigen-specific antibodies in mice immunized with 4-hydroxy-3-nitrophenylacetyl ovalbumin (NP-OVA) and dampened germinal center responses. Chronic GVHD by the transfer of CD8+-depleted splenocytes from C57BL/6 mice into BDF1 mice induces lupus-like symptoms including the induction of autoantibodies and immune complex-mediated nephritis. PD-1 agonist antibody alleviated the induction of anti-dsDNA Ab in the lupus model along with the suppression of germinal center formation. In conclusion, agonistic anti-PD-1 antibodies can effectively prevent autoantibody production and represent unique therapeutic agents in the treatment of autoimmune diseases.