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Engineered antigen-specific regulatory T cells

University of British Columbia

Achieving transplant tolerance with regulatory T cell (Treg) adoptive immunotherapy is currently under investigation as a therapy to reduce graft rejection, improve long-term outcomes, and patient quality of life. Initial approaches involve expansion of naturally-occurring Tregs, either polyclonal or antigen-specific, however both of these approaches have several technical limitations that restrict implementation at a large-scale. To circumvent these limitations, this work describes an alternate approach to generate antigen-specific Tregs by expressing a chimeric antigen receptor specific for HLA-A*02:01 (A2-CAR), which activates Tregs in the presence of HLA-A*02:01, a tissue antigen allele that is commonly mismatched between transplant donor and recipient. In the first CAR Treg studies, the antigen-binding region (scFv) of the A2-CAR was derived from the mouse BB7.2 hybridoma, which could cause immunogenic responses and limit its efficacy in humans. Additionally, most CAR Treg studies to date employ CD28 and CD3 signaling domains to activate the cell, but alternative co-receptor signaling moieties have not been adequately tested. Two major improvements to CAR Treg technology are explored: (1) the scFv is humanized to reduce the immunogenicity of the CAR construct itself, rendering it less likely to cause immune responses in humans and (2) a collection of a variety of co-receptor intracellular domains are tested in place of CD28 to determine whether alternative signals can bestow Tregs with more beneficial functional properties. In the final chapter, a method for staining FOXP3, the Treg master transcription factor, using mass cytometry is described to enable thorough tracking of FOXP3⁺ Tregs and the rest of the immune compartment in patient samples from various tissues. Collectively, this body of work furthers our understanding of Treg immunotherapies and provides further support for their use in transplant settings.

Text

2019-10-07

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/71844

Experimental Medicine

University of British Columbia

UBCV

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