Project 170761

Islet transplantation alleviates the need for daily insulin injections in Type-1 Diabetes. However, continuous immunosuppressive therapy to prevent the recipient's immune system from rejecting the islets can generate severe heath complications. To make islet transplantation safer and more widely applicable it will be necessary to learn how to make the patient's immune system tolerate the transplant. In essence, the goal is to apply to donor tissue the mechanisms that our immune system uses to prevent itself from attacking our own tissues (mechanisms of self tolerance that prevent autoimmune diseases). The ability to induce such immunological tolerance would dispense with the need to use continuous toxic immunosuppressive drug therapy to prevent islet rejection. However, we need to have much more knowledge about the natural mechanisms of immunologic tolerance if we are to apply them to donor transplants successfully. To study the mechanisms of natural tolerance we use mice with a genetically engineered immune system (transgenic and gene knockout technology), allowing us to track the fate of immune system cells with the potential to attack donor tissue. We have discovered three conditions where immune system cells can be naturally tolerant (tolerant without drug treatment) of a donor islet transplant and cells surrounding the transplant. Our goal will be to determine the cellular and molecular details of the mechanisms involved in generating these natural states of immunologic tolerance. The data generated should help provide a better understanding the control of tolerance and immunity to transplants and open new avenues for treatment of diseases such as Type-1 Diabetes via tissue transplantation.

using genetically engineered mouse models to study natural mechanisms of peripheral tolerance to self and alloantigens