Autoimmune diabetes and the circle of tolerance

Abstract

The concept of immunological tolerance is central to our understanding of type 1 diabetes and the development of strategies for its prediction, prevention, and cure. Tolerance simply refers to the absence of an immune response. Most of us are born with an immune system that develops tolerance to all the other systems of our bodies as well as to the things that we eat. It is the loss of immunological tolerance that leads to autoimmunity. And when that autoimmune response directly or indirectly targets the beta-cell, type 1 diabetes is the result. In the U.S., 1 in 600 of us loses tolerance to pancreatic beta-cells. Interference with T-cell function after the loss of tolerance, as can be achieved with immunosuppressive drugs like cyclosporin, arrests the disease, but the cost in side effects is high. Clearly, stopping the loss of tolerance would be preferable. If we can stop the loss of tolerance, we can prevent the disease. We and many others have investigated both approaches. But what of the people who already have diabetes? For them a separate but related strategy, tolerance induction, is required. Specifically, islet transplantation tolerance induction holds out the promise of being able to cure the disease. This has been the ultimate goal of our laboratory's work for the past two decades.