A Novel Tolerogenic Antibody Targeting Disulfide-Modified Autoantigen Effectively Prevents Type 1 Diabetes in NOD Mice

Abstract

Increasing evidence suggested that the islet amyloid polypeptide (IAPP) is an essential autoantigen in the pathogenesis of type 1 diabetes (T1D) in humans and non-obese diabetic (NOD) mice. A unique disulfide containing IAPP-derived peptide KS20 is one of the highly diabetogenic peptides in NOD mice. The KS20-reactive T cells, including prototypic pathogenic BDC5.2.9, accumulate in the pancreas of prediabetic and diabetic mice and contribute to disease development. We generated a monoclonal antibody (LD96.24) that interacts with IAg7-KS20 complexes with high affinity and specificity. LD96.24 recognized the IAg7-KS20 disulfide loop and blocked the interaction between IAg7-KS20 tetramers and cognate T cells but not other autoantigen-reactive T cells. Thein vivoLD96.24 studies, at either early or late stages, drastically induced tolerance and delayed the onset of T1D disease in NOD mice by reducing the infiltration of not only IAPP-specific T cells but also chromogranin A and insulin-specific T cells in the pancreas, together with B cells and dendritic cells. LD96.24 can also significantly increase the ratio of Foxp3+regulatory T cells with Interferon-gamma-secreting effector T cells. Our data suggested the important role of disulfide-modified peptides in the development of T1D. Targeting the complexes of Major histocompatibility complex (MHC)/disulfide modified antigens would influence the thiol redox balance and could be a novel immunotherapy for T1D.