Th192 - Therapeutic Treatment with PLGA Nanoparticles Containing a Single CD4+ Epitope Reverses CD8+ T Cell-induced Type I Diabetes Disease Progression

Abstract Text: Type 1 diabetes (T1D) is characterized by T and B cell responses to pancreatic β islet cell proteins, insulitis, and β islet cell loss. While, tolerance induction to individual diabetogenic proteins, e.g., GAD65 or insulin, has failed to ameliorate T1D both in wildtype NOD mice and T1D patients, treatment of NOD mice with poly(lactic-co-glycolic acid) (PLGA) nanoparticles (COUR CNPs) containing recombinant insulin, GAD65, and chromogranin A proteins (CNP-T1D) inhibited antigen (Ag)-specific T cell responses and disease progression. The ability of therapy to regulate CD8+ T cell activity and the subsequent disease progression due to CD8+ T cells was unknown. Our data show that treatment of NOD mice with TIMPs containing whole diabetogenic antigens results in an increased number of CD4+ and CD8+ T cells expressing regulatory markers and a decrease in disease incidence. While these findings show that Ag-specific treatment can modulate CD8+ T cells, these effects may or may not require CD4+ Tregs. Therefore, we sought to determine if treatment of mice with TIMPs containing only a single CD4+ T cell peptide epitope within the same protein could result in modulated CD8+ T cell function. Utilizing the OTI CD8+ T cell transfer into RIP-mOVA mouse model of T1D, mice were treatment with unloaded TIMP vs TIMP-OVA323, i.e., a dominant CD4+ T cell epitope, when mice had an average blood sugar of >225 mg/dL. The data show that TIMP-OVA323 treatment restored my to euglycemia for ~9 weeks in a Treg-dependent manner, and anti-CD25 treatment block tolerance