Shapiro, Michael J

Abstract Cell surface hypersialylation is used by malignant cells as a survival mechanism, leveraging interactions with Siglec receptors to dampen the immune response. In this study, we aimed to harness this mechanism to prevent autoimmune rejection of beta cells in the context of type 1 diabetes. Mice engineered to overexpress the sialyltransferase ST8Sia6 in beta cell (BST) were generated and crossed to the non-obese diabetic (NOD) mouse for 10 generations. The blood glucose of these mice compared to non-overexpressing littermates was assessed twice weekly to determine diabetes incidence, defined as 3 consecutive blood glucose readings above 250 mg/dL. Analysis of female BST mice aged 15 weeks or greater showed no incidence of overt diabetes, while littermates developed diabetes. BST males aged 15 weeks or greater also had no disease incidence, while littermate controls also became diabetic. An insulin tolerance test demonstrated no significant difference between BST mice and littermates, though the BST had significantly higher blood glucose during a glucose challenge, possibly representing insulin hypersecretion by littermate islets in a stressed pre-diabetic state. Histologic analysis of young BST and littermate pancreata showed no differences, with similar levels of insulitis at 8 weeks. Thus, the overexpression of ST8Sia6 has been shown to mitigate autoimmune attack in the NOD model and presents a novel path forward for prevention of islet transplant rejection.