Development of a Novel Antigen-Specific Therapy for Autoimmune Diabetes Using an Insulin-ChgA Hybrid Peptide Neoantigen

Abstract

Abstract In Type 1 Diabetes (T1D) patients and non-obese diabetic (NOD) mice, autoreactive CD4 T cells contribute to destruction of insulin-producing β-cells in the pancreatic islets. Our lab has discovered that in NOD mice the endogenous ligand for the diabetogenic CD4 T cell clone BDC-2.5 is a hybrid insulin peptide (2.5HIP), consisting of a fragment from proinsulin fused to a peptide from chromogranin A (ChgA). The purpose of this study was to determine if tolerogenic poly(lactide-co-glycolide) (PLG) nanoparticles (NPs) coupled with 2.5HIP (2.5HIP-PLG) could be used to induce antigen-specific T cell tolerance. We have found that treatment with 2.5HIP-PLG NPs synergizes with a short course of low-dose recombinant IL-2, leading to robust induction of 2.5HIP-specific Foxp3+ regulatory T cells (Tregs) and prevention of spontaneous diabetes in 50% of NOD mice. In a disease reversal model, spontaneously diabetic NOD mice were transplanted with 500 syngeneic islets and recipients were infused with HEL-PLG (control) or 2.5HIP-PLG NPs pre- and post-transplant. In contrast to HEL-PLG treated mice that showed aggressive disease recurrence in around 2 weeks, graft destruction in 2.5HIP-PLG treated mice was significantly delayed up to an average of 8 weeks, indicating that targeting graft-infiltrating 2.5HIP-specific T cells dampens ongoing autoimmunity. Our current goal is to determine whether the therapeutic effects observed in the transplantation model are due to expansion of antigen-specific Tregs, induction of anergy in effector T cells, or both. This novel antigen-specific therapy using a disease-relevant neoantigen may have implications for development of an immune-modifying treatment for T1D patients.