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Wardell, Christine Marie

University of British Columbia

A major barrier to transplantation success is the recipient’s transplant-reactive “alloimmune” response which detects and kills non-self graft tissue. Currently, transplant recipients are placed on broad immunosuppressive regimens that increase the risk of infection and cancer. There is a critical need for therapies that specifically target and inhibit transplant recipients’ alloimmunity while leaving beneficial immune responses intact. Due to their polymorphic nature, human leukocyte antigens (HLA) are often mismatched between transplant donor and recipient, and are major targets of the alloreactive response. In this dissertation, I investigated how we can use T cells to detect and prevent allo-HLA-reactive responses, as well as local autoreactive responses. I developed an assay to quantify and correlate peripheral alloreactive T cells with transplant biopsy results. I designed the assay based on a concept called “trogocytosis”, whereby immune cells acquire and re-express proteins following a strong immune synapse. I hypothesized that allo-HLA-reactive T cells trogocytose mismatched allo-HLA molecules, therefore tagging themselves as alloreactive in a way that is detectable by flow cytometry. I tested the assay on blood from kidney transplant recipients that was paired with surveillance biopsy histological scores. I also developed two mouse models of type 1 diabetes and transplantation to assess whether regulatory T cells (Tregs) expressing a chimeric antigen receptor that detects HLA-A2 (A2-CAR Tregs) could protect HLA-A2⁺ islet transplants against allo- and autoimmunity. I hypothesized that A2-CAR Tregs would reduce the incidence of transplanted HLA-A2⁺ islet rejection in diabetic HLA-A2negative mice, and in turn, induce tolerance in diabetogenic autoimmune cells that target common islet antigens. I showed that A2-CAR Tregs were effective at preventing hyperglycemia in an aggressive autoimmune diabetes mouse model via linked suppression and infectious tolerance, providing evidence that Tregs can reshape immunity in a persistent manner. Although HLA mismatch between transplant donor and recipient can spur an alloimmune response that quickly destroys graft tissue, donor HLAs can be used as an abundantly-expressed immunotherapeutic target. My Ph.D. studies demonstrated how to harness T cells that detect mismatched HLA molecules to monitor and prevent transplant rejection, mediated by both allo- and autoreactive immune cells.

Text

2024-07-23

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88679

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/