Grant: Doctoral Research Award: Canada Graduate Scholarships

During transplant rejection or autoimmune attack, the body's immune balance is disrupted. Specifically, two types of immune cells are out of balance - inflammatory conventional T cells and immune-suppressive regulatory T cells (Tregs). Unlike standard immunosuppressive drugs, which depress the entire immune system, Treg cell therapy can restore immune balance and promote localized immune suppression without affecting normal immune responses. Unfortunately, Tregs are very rare, hard to purify, and their quality/function varies between patients; thus, making it difficult, expensive, and time-consuming to obtain patient-specific Tregs and expand them into a therapeutic dose. We aim to solve the above issues by exploring two different sources of donor-derived Tregs that could be pre-made and stored frozen for use as needed. (1) We have shown that we can use human thymuses, which are routinely removed and discarded during pediatric heart surgery, as a rich source of Tregs. However, Tregs are still heterogenous within the thymus and we want to find out how to make even more pure cells for the best cell therapy product. We will do this by finding new ways to separate different Treg subsets in the thymus and identify the optimal subset for suppression of inflammation and cell therapy use. (2) Pluripotent stem cells (PSCs) are cells that can mature into any cell type within the body - given the right stimuli. We developed a protocol that mimics Treg development in the thymus in vitro (using molecules that enforce Treg identity) in order to generate Treg-like cells from PSCs (PSC-Tregs). We aim to compare PSC-Tregs with Tregs made in the thymus for their ability to suppress inflammation and be genetically-modified to enhance their functionality. Overall, this study will create new ways to make readily-available Treg cell therapies more feasible to treat patients with autoimmunity or transplant rejection while minimizing manufacturing constraints.