Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which pathogenic lymphocytes target autoantigens expressed in pancreatic islets, leading to the destruction of insulin-producing b-cells. Zinc transporter 8 (ZnT8) is a major autoantigen abundantly present on the b-cell surface. This unique molecular target offers the potential to shield b-cells against autoimmune attacks in T1D. Our previous work showed that a monoclonal antibody (mAb43) against cell-surface ZnT8 could home in on pancreatic islets and prevent autoantibodies from recognizing b-cells. This study demonstrates that mAb43 binds to exocytotic sites on the b-cell surface, masking the antigenic exposure of ZnT8 and insulin after glucose-stimulated insulin secretion. In vivo administration of mAb43 to NOD mice selectively increased the proportion of regulatory T cells in the islet, re-sulting in complete and sustained protection against T1D onset as well as reversal of new-onset diabetes. The mAb43-induced self-tolerance was reversible after treatment cessation, and no adverse effects were exhibited during long-term monitoring. Our findings suggest that mAb43 masking of the antigenic exposure of b-cells suppresses the immunological cascade from B-cell antigen presentation to T cell–mediated b-cell destruction, pro-viding a novel islet-targeted and antigen-specific immu-notherapy to prevent and reverse clinical T1D.