- Dr David M. Rothstein, Principal Investigator
- Yale University, New Haven, USA
- How Experimental Agents Prevent Islet Transplant Rejection by Inducing Different Types of Regulatory T Cells
Transplantation is the treatment of choice for end-stage disease of organs including heart, kidney, and pancreas. Despite great progress, life-long therapy with immunosuppressive medications is required to prevent rejection. However, these medications increase the risks of infection and malignancy, in addition to risks of kidney damage, high blood pressure, and cardiovascular disease. As such, pancreas or islet transplantation is frequently reserved for diabetic patients who already display significant damage to their kidneys or other organs. Therefore, approaches that can induce immune tolerance (i.e. limited therapy designed to “trick” the immune system into accepting the transplant as self rather than foreign tissue) would not only promise to improve outcomes, but would lower risks of infection, cancer and kidney damage, currently associated with chronic immunosuppression. For example, this would make islet transplantation accessible to younger diabetic patients, before the onset of damage to other organs, such as the kidney.
Various approaches can induce transplant tolerance in experimental animals. Many such approaches appear to augment regulatory T cells (Treg) in the immune system. These cells inhibit immune responses, and might dampen autoimmunity or prevent transplant rejection. Thus, there has been great interest in understanding how these cells can best be manipulated for therapeutic gain. However, understanding has been limited because there are different types of Treg that are difficult to identify and appear to act in distinct manners. In this proposal, we will use novel genetically engineered mice whose regulatory cells fluoresce red. This will allow us to confirm whether individual tolerance-inducing strategies actually induce Treg and if so, how this occurs. This will provide critical insights into the generation and function of Treg and ultimately allow us to understand how they can best be manipulated for the induction of immunological tolerance in islet transplantation.