Nanoparticles Containing an Insulin-ChgA Hybrid Peptide Prevent Transfer of Type 1 Diabetes in NOD Mice by Expanding Foxp3+ Tregs

Abstract

Abstract In Type 1 Diabetes (T1D) autoreactive T cells destroy insulin-producing β-cells in the pancreatic islets. A major focus of our lab has been to identify novel peptide ligands for diabetogenic CD4 T cells isolated from non-obese diabetic (NOD) mice. We have identified a novel post-translational modification whereby a peptide from chromogranin A is covalently bound to a fragment from proinsulin, resulting in formation of a hybrid insulin peptide (2.5HIP) that is a potent ligand for the CD4 T cell clone BDC-2.5. Using an MHC class II tetramer to track the frequency and phenotype of endogenous 2.5HIP-reactive T cells in NOD mice, we found that these cells play a critical role in the disease process. The purpose of this project was to determine if poly(lactide-co-glycolide) (PLG) nanoparticles (NPs) loaded with 2.5HIP could be used to prevent induction of diabetes by transfer of BDC-2.5 TCR transgenic T cells cells into NOD.scid mice. We have found that i.v. infusion of 2.5HIP-coupled NPs (2.5HIP-PLG) one day after T cell transfer can almost completely prevent diabetes. Treatment with 2.5HIP-PLG leads to reduced T cell trafficking to the pancreas early on, as well as in vivo expansion of long-lived Foxp3+ regulatory T cells (Tregs) that express inhibitory receptors, membrane bound TGFβ-1/LAP, and stability markers. We predict that stable long-lived Tregs are critical for suppressing pathogenic IFN-γ producing T cells and maintaining long-term tolerance in this system. The end goal of this study is to determine if NPs containing HIPs can be used to prevent and/or reverse spontaneous disease in NOD mice. Results from these studies could have significant implications for the development of an antigen-specific therapy for T1D patients.