Grant: Project Grant

In the past 10 years, more than 20,000 Canadians have had their lives improved or saved by receiving transplant of donated organs. Transplantation is the best treatment for some conditions (cancer, organ failure). It is possible only possible because immunosuppressive drugs prevent rejection. At the same time, these drugs also bring risk of infection, cancer, and other side effects. Our goal is to find ways to "educate" the patient's immune system to accept a transplanted organ in a way that reduces the need for and toxicity of immunosuppression. We will harness the natural properties of a type of white blood cell called a T regulatory cell (Treg). Tregs modulate the immune system to prevent overactivity of unwanted responses. Tregs have the potential to be used to limit immunity to transplanted tissues and organs. Recently, by introducing an artificial protein called a chimeric antigen receptor (CAR), we developed a new way to maximize the ability of Tregs to control the person's immunity to transplants. These CAR Tregs are being used in clinical research studies. But we still need to know many things, including: how to integrate the approach with current treatments, and how to optimize CAR Treg functions and effects. In this project, we will use transplantation studies in mice to address these questions. First, we will see if /how to use CAR-mediated cell signals to enable combination with less toxic immunosuppression. Then we will study how CAR Tregs affect the recipient's immune responses to the transplanted tissue. Finally, we will test new genetic modification strategies that we think could make CAR Treg therapy even better. Our results will help in the design and testing of Tregs as a new therapy in transplantation. By creating new ways to minimize need for immunosuppressive drugs, our research has the potential to improve the long-term success of transplantation.