Grant: Doctoral: Vanier Canada Graduate Scholarships

Megan Levings, University of British Columbia Organ transplantation is life-saving for people with severe organ failure. Since the immune system sees the new organ as foreign and attempts to destroy it, transplant recipients must take immunosuppressive drugs for the rest of their lives to prevent rejection. Unfortunately, these drugs prevent the immune system from carrying out its normal functions, placing transplant recipients at high risk of infection and cancer. Regulatory T cells (Tregs) are specialized immune cells that specifically suppress unwanted immune responses. As such, using Tregs as a cell therapy, by infusing the cells into a transplant recipient's bloodstream, is a promising approach to preventing transplant rejection. Treg therapy is safe, with few side effects, but there are several challenges to address. For example, Tregs do not survive and persist long-term after infusion, and become 'exhausted' with constant overstimulation, causing them to lose immune-suppressive function over time. To address this, my work aims to improve Treg therapy by increasing potency and specificity, and improving how long Tregs persist and remain effective in the body. I will use genetic engineering to alter Tregs so they can specifically target a molecule called MHC II. MHC II is found on types of immune cells that contribute to transplant rejection by producing antibodies and activating immune cells targeting the new organ. Because MHC II levels in transplanted organs are low at baseline but increase with inflammation, Tregs targeting MHC II could be less likely to become exhausted: instead of receiving constant overstimulation, they would specifically receive MHC II stimulation when needed, during inflammatory rejection of the transplanted organ. Ultimately, my goal is to improve Treg therapies to eventually replace or reduce the need for immunosuppressive drugs, decreasing mortality and improving quality of life for people who undergo organ transplantation.