Diabetes and other autoimmune endocrine diseases
Antigen-specific immunotherapies (ASIT) are among the safest approaches to treat/prevent Type 1 diabetes (T1D) but so far have shown poor efficacy when tested in clinical trials. It is becoming evident that neoepitopes play an important role in driving T1D and may also be clinically relevant as they are often not present in healthy tissues. However, whether they have utility as part of ASITs remains to be determined. In this study, we evaluated a Soluble Antigen Array (SAgA) therapy that bundles ~10 copies of a peptide on a single hyaluronic acid (HA) backbone for late stage prevention of diabetes in the NOD mouse model of T1D. A mix of two SAgAs carrying a hybrid peptide of insulin and chromogranin A, and the p79 mimotope efficiently prevented the onset of autoimmune diabetes (p=0.0003) while each single SAgA failed to provide any significant delay or protection on its own. SAgAs elicited more robust antigen-specific T cell responses to SAgA-derived peptides as compared to equimolar doses of their corresponding free peptides. Mechanistically, SAgAs induced the upregulation of IL-10 and anergy / exhaustion markers (PD-1+, FR4+ CD73+) in antigen-specific T cells. Interestingly, this phenotype was enhanced when the linker used to graft peptides on HA was non-hydrolysable. The HA carrier itself, an FDA-approved biopolymer, also slightly reduced the incidence of diabetes (p=0.03) as compared to control mice, possibly as a result of an anti-inflammatory effect of HA. In sum, SAgAs constitute a novel and promising ASIT platform for the prevention of T1D.