ST8Sia6 attenuates diabetes progression and severity

Abstract

Abstract Nearly 1.25 million Americans suffer from type 1 diabetes, an autoimmune disease which destroys insulin-producing beta cells of the pancreatic islets. Although insulin therapy is a lifesaving treatment, it is not a cure and secondary complications remain a significant concern. Experimental islet transplantation as a curative measure has yet to overcome the barrier of immune-mediated destruction, as patients eventually revert back to insulin-dependency. Immunotherapies to date have focused on targeting the adaptive immune response, largely ignoring the innate immune system, and have had limited success. Siglec-E is an inhibitory receptor expressed on innate immune cells such as macrophages and dendritic cells; it is known to dampen inflammation through several mechanisms. Here, we demonstrate that the sialic acid transferase ST8Sia6, which catalyzes addition of a2,8-linked disialic acids to glycoproteins, produces cell surface ligands for Siglec-E. We selectively expressed ST8Sia6 in pancreatic beta cells, hypothesizing this would have a beneficial effect in delaying disease in the murine multiple low-dose streptozocin model of diabetes. We observe that when diabetes is induced, mice that express ST8Sia6 in beta cells have delayed onset of diabetes and less severe hyperglycemia as compared to littermate controls. Notably, expression of ST8Sia6 in beta cells does not interfere with normal glucose response. Therefore, ST8Sia6 expression in pancreatic beta cells is safe and attenuates diabetes progression and severity. Because cell surface glycans play a major role in recognition of self, this work has significance in islet-targeted gene therapy, transplantation, and graft survival.