Early exposure to frequent microbial infections prevents both spontaneous and immune checkpoint inhibitor-induced autoimmune diabetes 4408

Abstract Description It has been difficult to study contextually how infections may trigger or prevent autoimmune diabetes because diabetes mouse models are kept in specific pathogen-free (SPF) environments, which do not accurately correlate to an human’s natural immunologic environment. In this context, NOD mice develop spontaneous autoimmune diabetes in SPF conditions. We used a ‘dirty animal’ model, where NOD mice were housed with fomite bedding from pet store mice, resulting in a physiologically relevant environment characterized by frequent and varied infections. We observed complete protection from diabetes by subjecting NOD mice to a normalized microbial experience (NME) despite persistent immune cell infiltration around pancreatic islets, suggesting that auto-reactive T cells were still present but restrained from activation peripherally. The inhibitory receptor PD-1 and its ligand PD-L1 are one known mechanism by which peripheral tolerance of auto-antigens are maintained, and pharmacologic blockade of these targets in human cancer immunotherapy increases risk of stimulating rapid autoimmunity, including T1D. We found that in protected NME-NOD mice, PD-L1 blockade stimulated a rapid, destructive insulitis and diabetes onset that required new T cell infiltration. Ongoing studies are now characterizing the relevant pathogens and T cell populations in this NME-NOD model to identify cellular and molecular targets that can be exploited for future immunotherapies for patients at risk for T1D. Funding Sources Zachary Shaheen: supported by JDRF 1-INO-2024-1539-A-N Brian Fife: supported by R01AI156276, P01AI035296, R21AI166475, Helmsley Charitable Trust Topic Categories Basic Autoimmunity (BA)