Grant: Project Grant

Transplantation is a life-saving treatment for people facing organ failure. Transplants are only possible because there are drugs that suppress the recipient's immune system to prevent rejection. But while suppressing the immune system prevents rejection, it dramatically increases the risks for infection, cancer, and other side effects. Our goal is to find ways to teach the patient's immune system to accept the transplant which will reduce the need for immune suppressing drugs. Our strategy is to harness the natural immune regulating properties of a type of white blood cell called T regulatory cells (Tregs), which prevent overactivity of unwanted immune responses. Our strategy is to use gene engineering to introduce a synthetic immunoreceptor that binds to a protein found in the donor not the recipient. The immunoreceptor is called a chimeric antigen receptor, or CAR. CAR Tregs are directed to the transplant, localizing their function where it is needed. As a next step to develop CAR Treg therapies with the best chance of working in patients, we need to understand more about how these cells work to control immune responses. We will study how CAR Tregs re-shape immune responses in transplantation. First, we will study how different types of CAR Tregs affect anti-transplant immune responses. Then we will test different engineering strategies to enhance and tailor their function. We will set up a new, multi-cellular method to study immune responses to transplants. These studies will help us to understand more about how CAR Tregs work, and how to modify them for even better effects. They will also generate key proof-of-concept studies that will be used to inform future studies of CAR Tregs in human transplantation. Overall, by creating 'designer' Tregs specifically modified for better function, our work has potential to improve the long-term success of transplantation.