Therapeutic treatment with PLGA nanoparticles containing a single CD4+ epitope reverses CD8+ T cell-induced type I diabetes disease progression 3303

Abstract Description Autoimmune diseases, such as multiple sclerosis and type-1 diabetes (T1D), are mediated by autoantigen-specific CD4+ and CD8+ T cells. Treatment with antigen (Ag)-containing biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles, i.e. tolerogenic immune-modifying particles (TIMP, also denoted as CNPs), induces Ag-specific tolerance. While extensive work has shown the effect of Ag-specific TIMP treatment on CD4+ T cells, less is known on how Ag-specific TIMP treatment regulates CD8+ T cell activity. 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, a decrease in disease incidence, and significantly decreases the number of T cells present within the pancreas. 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 B6.RIPmOVA 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 induction. Funding Sources This work was supported by grants to S.D.M. from Cour Pharmaceutical Development Company, NIH grant R01AI148076; and by gifts from the Johnnie Walkers MS Foundation, the Amy and David Fulton Foundation, the Crammer Family Foundation, the Thomas and Deige McLaughlin Foundation, and the Rottering Family Foundation. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)