Therapeutic treatment with a single CD4+ T cell epitope containing PLGA nanoparticles reverses CD8+ T Cell induced Type I Diabetes 2260609

Abstract

Abstract Introduction T cell-mediated autoimmune diseases, such as type I diabetes (T1D) are mediated by autoantigen-specific CD4+ and CD8+ T cells. We have pioneered CD4+ T cell antigen (Ag)-specific tolerance induction therapy via biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles (also knowns as TIMPs/CNPs) treatment. While TIMP/CNPs have progressed into Phase I/IIa clinical trials in celiac disease, myasthenia gravis, primary biliary cholangitis, and T1D, less is known about how treatment regulates CD8+ T cells. Methods Therefore, the RIP-mOVA mouse model of T1D was presently used to mechanistically address remaining questions. Following OTI CD8+ T cell-induced early onset T1D. Results Following OTI CD8+ T cell-induced early onset T1D, a single dose of CNP-OVA323, i.e., a CD4+ T cell epitope, reversed dysglycemia/T1D in a regulatory T cell-dependent manner for up to 9 weeks post dosing. Of note, CNP-OVA323 treated mice develop a secondary dysglycemia at this timepoint. An event hypothesized to be driven by early IFN-γ-induced beta cell death resulting in spread epitope-specific CD4+ T cell activation during the initial dysgycemic event. As confirmation, treatment with CNP-T1D (containing Ag for the spread epitope-specific T cells) inhibited the development of secondary dysgycemia. Data presented will track the transferred OTI T cells over time, ex vivo recall responses to beta cell expressed proteins during secondary dysgycemia, and the ability of CD4+ T cells to regulate autoreactive CD8+ T cell responses post Ag-specific TIMP treatment. Conclusion CNP containing CD4 Epitopes from Ag’s are able to regulate CD8 T cell responses to the same Ag’s. Furthermore, inclusion of spread epitopes in a second dose of CNP are able to regulate secondary dysglycemia in the RIP-mOVA mouse model of T1D. Funding Source Breakthrough T1D Topic Categories Therapeutic Approaches to Autoimmunity (THER)