Autoantigen-Specific Immunotherapy

The incidence of type 1 diabetes (T1D) is increasing dramatically and new treatment modalities are needed urgently. Arising from autoimmune destruction of the pancreatic ┚cells, T1D manifests itself when less than 10-20% of functional ┚-cells remain in the islets and is characterized as a disorder of glucose regulation due to the insufficient production of insulin. Insulin is a hormone secreted by pancreatic islet ┚-cells and its main function is to move blood sugar into cells where it is stored and later used for energy. In T1D, the ┚-cells are destroyed by the patients’ immune cells leading to limited or no insulin production. Without enough insulin, glucose accumulates in the bloodstream instead of entering the cells, causing symptoms of hyperglycemia. Chronic hyperglycemia can lead to many serious complications. Insulin replacement therapy is the current standard for treatment involving injection of recombinant insulin. Normal pancreatic insulin secretion is exquisitely sensitive to the minute-to-minute changes in blood glucose and glucose-stimulated insulin secretion (GSIS) and cannot be mimicked precisely by exogenous insulin injections. Thus, while insulin treatment successfully prolongs the life of affected individuals, it fails to prevent some of the serious complications of T1D that adversely affect quality of life and ultimately lead to significant morbidity and mortality. An alternative promising therapy is islet cell transplantation, but this suffers from several drawbacks including limited pancreatic islet tissue from cadaveric donors, the requirement for lifelong immunosuppression, and the increased risk of infection due to non-specific suppression of the immune system. To cure T1D, researchers are pursuing combined immunological and biological strategies for restoring ┚-cell mass. Strategies for increasing ┚-cell mass include promoting endogenous pancreatic ┚-cell regeneration, reprogramming non-pancreatic cells into insulin-producing cells (IPCs), and generating unlimited autologous pancreatic ┚-cells from induced pluripotent stem (iPS) cells of the T1D patients. At the same time, there is considerable interest in approaches for modulating and suppressing autoimmunity to pancreatic ┚-cells and surrogates of IPCs. An individual’s pancreatic ┚-cell mass is tightly regulated according to insulin demand, reflecting a balance between the rate of ┚-cell replication, regeneration/reprogramming, and the rate of ┚-cell apoptosis. Research efforts are focusing on how best to expand, reprogram, or generate ┚-cells or their surrogates from pancreatic stem/precursor cells, non-pancreatic adult/stem cells, or the iPS cells of T1D patients for ┚-cell replacement therapy. However, without preventing ongoing autoimmune