Induction of antigen-specific tolerance with Hybrid Insulin Peptides in the NOD mouse model of autoimmune diabetes

Abstract

Abstract In Type 1 Diabetes (T1D), autoreactive CD4 T cells are important contributors to the inflammatory infiltrate in the pancreatic islets which leads to the destruction of insulin-producing β-cells. We recently found that CD4 T cell lines and clones isolated from non-obese diabetic (NOD) mice and T1D patients are strongly activated by novel peptide ligands which are hybrid insulin peptides (HIPs) consisting of proinsulin fragments fused to other peptides present in β-cell secretory granules. Our data suggest that HIPs play a central role in the pathogenesis of T1D and we hypothesize that loss of tolerance to the pancreatic islets involves HIP-reactive T cells. In this project we have investigated whether HIPs can be used for the induction of antigen-specific tolerance in NOD mice. The specific objective is to determine whether HIP-loaded biodegradable nanoparticles can prevent disease transfer by diabetogenic T cells into NOD mice. Our experimental system involves HIPs coupled to or encapsulated within poly(lactide-co-glycolide) (PLG) nanoparticles which are administered to NOD mice following injection of BDC-2.5 TCR transgenic T cells to trigger disease. Preliminary data from these experiments indicates that a hybrid between an insulin C-peptide sequence and a peptide from ChgA can completely block transfer of BDC-2.5 diabetogenic T cells. Long-term goals of this project are (1) to test the ability of nanoparticles containing other HIPs in preventing transfer of diabetogenic T cells and (2) to determine whether HIP-loaded nanoparticles are capable of reversing spontaneous disease in NOD mice. Results from these studies could have significant implications for the development of antigen-specific therapy in T1D.