Inhibition of autoimmune diabetes by ST8Sia6

Abstract Autoimmune diseases can occur in nearly any part of the body, and pose a significant problem in human health, including both systemic autoimmunity and tissue-specific autoimmunity. 1.25 million Americans have type 1 diabetes (T1D), where the immune system destroys insulin-producing beta cells. Although exogenous insulin can control blood glucose levels in patients with diabetes, glucose homeostasis is difficult to maintain and serious long-term complications including nephropathy, retinopathy, and peripheral neuropathy are far too common. Since the first procedure using the Edmonton protocol in 1999, islet transplantation has established itself as a promising therapy for patients with longstanding T1D, and beta cell replacement using replenishable sources like human embryonic stem cell-derived beta cells has the potential to become curative. Islet transplantation requires a drug regiment to suppress the immune response from allorejection as well as autoimmune attack against pancreatic b cells, resulting in chronic immunosuppression with its own severe complications, exposing patients to risk of infection and malignancies. Immunotherapies that provide local inhibition of immune response to the graft, without systemic immune inhibition, are a critical need. Immune cells have receptors that can either activate or suppress an immune response. Sialic acids incorporated into glycans have the ability to bind to a family of predominantly inhibitory receptors on the surface of many immune cells. We have shown that the sialic acid transferase ST8Sia6 generates ligands for the inhibitory receptor Siglec-E, which is expressed on innate immune cells. In addition, our work demonstrated that ST8Sia6 expression on tumor cells leads to enhanced growth and protection from the immune response. Here, we generated a novel line of mice in our laboratory where ST8Sia6 is constitutively expressed in pancreatic b cells in the NOD mouse model of Type 1 diabetes (“NOD bST mice”). NOD bST mice are strongly protected from the development of diabetes; only 6% of NOD bST female mice became diabetic as compared to 60% of NOD female littermate controls. Strikingly, NOD bST mice possessed a durable tolerance towards b cells, as protection was maintained after ST8Sia6 expression was inhibited with doxycycline. The focus of this proposal is to understand the changes in the immune response that occur with ST8Sia6 expression in b cells, and whether ST8Sia6 expression on b cells provides enhanced protection from immune attack after transplantation. By doing these experiments in mice, important information will be gained that may be translated to the clinic for islet replacement therapy for patients with T1D.