Grant: CIHR Fellowship

Solid organ transplantation (SOT) is a curative option for end stage organ failure; however, the success of this procedure depends on life-long use of immunosuppressive drugs which put patients at risk for infections and cancer. Regulatory T cells (Treg) are immune cells that favour the acceptance of the transplanted organ by the recipient's immune system. One way to increase the numbers of organ-protective Tregs is to isolate them, expand them in the lab, and then re-infuse them into patients. A limitation, however, is that it is difficult to isolate Tregs that are specifically able to suppress immune responses to a transplant. Recently, we developed a revolutionary way to overcome this limitation using a genetic engineering strategy in which organ-specific Tregs can be made by introducing a chimeric antigen receptor, or CAR. This project aims to optimize the function of CAR-Tregs by studying how to best design the CAR and to find ways to reduce risks associated with this strategy. My first goal will be to modify the CAR structure trying to find ways so mimic how Tregs would be naturally activated so their function and lifespan are optimal. I will also aim to reduce the risk of using CAR-Treg therapies. We have recently identified that CAR-Tregs which do not express a protein called Helios are prone to lose their ability to favour organ acceptance. We thus aim to engineer CARs in a way that they would only be expressed in Tregs which continue to express Helios. I will carry out these aims using experimental systems that are well-established. Significance: by optimizing CAR structure I will improve the function and lifespan of CAR-Tregs and also reduce their associated risks. The results generated in this study will inform the design of future clinical studies and will also help to facilitate the use of CAR-Treg-based therapies as a new therapeutic tool to diminish transplant rejection.