Harnessing T cells that detect mismatched HLA to monitor and prevent allo- and autoimmunity
department or school: Medicine, Faculty of
department or school: Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Wardell, Christine Marie
issued: 2024-07-23T15:41:28Z
issued: 2024
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: A major barrier to transplantation success is the recipientâs transplant-reactive âalloimmuneâ 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 recipientsâ 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 âtrogocytosisâ, 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-A2âº islet transplants against allo- and autoimmunity. I hypothesized that A2-CAR Tregs would reduce the incidence of transplanted HLA-A2âº 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…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/88679
note: HARNESSING T CELLS THAT DETECT MISMATCHED HLA TO MONITOR AND PREVENT ALLO- AND AUTOIMMUNITY by Christine Marie Wardell B.Sc., McMaster University, 2017 M.Sc., Western University, 2019 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Experimental Medicine) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2024 © Christine Marie Wardell, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: HARNESSING T CELLS THAT DETECT MISMATCHED HLA TO MONITOR AND PREVENT ALLO- AND AUTOIMMUNITY submitted by Christine Marie Wardell in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Experimental Medicine Examining Committee: Megan Levings, Professor, Surgery, UBC Supervisor Francis Lynn, Associate Professor, Surgery, UBC Supervisory Committee Member Ramon Klein Geltink, Assistant Professor, Pathology and Laboratory Medicine, UBC Supervisory Committee Member Gregor Reid, Associate Professor, Pediatrics, UBC University Examiner Kirk Schultz, Professor, Pediatrics, UBC University Examiner Additional Supervisory Committee Members: Robert Holt, Professor, Medical Genetics, UBC Supervisory Committee Member iii Abstract A major barrier to transplantation success is the recipientâs transplant-reactive âalloimmuneâ 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 recipientsâ 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 di…
has type: Thesis/Dissertation
date issued: 2024-11
is shown at: 10.14288/1.0444795
language: eng
degree discipline: Experimental Medicine
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Levings, Megan K.
type: Text
identifier URI: http://hdl.handle.net/2429/88679