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Permanent link (DOI): https://doi.org/10.7939/R3ZG6GJ51

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Proximal Impact of Transplant Tolerance-Promoting Antibody Therapies on Antigen-Specific T Cell Reactivity Open Access

Descriptions

Other title
Subject/Keyword
transplant survival
antibody therapy
immune tolerance
transplant
costimulation blockade
transplantation
T cells
transplantation tolerance
transplant tolerance
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Wang, Szu-I
Supervisor and department
Anderson, Colin (Medical Microbiology and Immunology)
Gill, Ronald (Medical Microbiology and Immunology)
Examining committee member and department
Baldwin, Troy (Medical Microbiology and Immunology)
Rothstein, David (University of Pittsburgh, Department of Immunology)
Barry, Michele (Medical Microbiology and Immunology)
Kane, Kevin (Medical Microbiology and Immunology)
Rayat, Gina (Medical Microbiology and Immunology)
Department
Department of Medical Microbiology and Immunology
Specialization
Immunology
Date accepted
2013-08-30T07:23:12Z
Graduation date
2013-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
The development of a transient, tolerance-promoting therapy is a critical goal in transplantation. Antibody-perturbation of T cell activation signals is considered a promising candidate. However, the mechanisms of such therapies remain vague. The lack of cohesive and systematic knowledge in the requirements of generating long-term transplantation tolerance using short-term antibody treatments impedes the rational design of tolerance-promoting therapies. Therefore, using anti-LFA-1 and anti-CD154 as representatives of efficacious tolerance-inducing therapeutics, I interrogated their proximal impact on naïve antigen-specific T cells during initial antigen encounter. Using both monoclonal TCR-transgenic and polyclonal T cells in an in vivo adoptive transfer model, I tracked T cell activation and differentiation in the presence of anti-LFA-1 and/or anti-CD154. The antibody therapies markedly reduced the number of T cells in the draining lymph nodes. However, those remaining in the nodes vigorously proliferated. This paradoxical decrease in cell number despite intact proliferative capability was not due to deletion, as the adoptively transferred T cells persisted past primary activation and responded productively to secondary antigen exposure. Surprisingly, while anti-LFA-1 and/or anti-CD154 partially inhibited effector cytokine production, they did not specifically induce differentiation of alternate, tolerogenic phenotypes. However, while the antibody therapies mediated neither complete suppression of T cell reactivity nor T cell tolerance, anti-LFA-1- and anti-CD154-mediated skin graft prolongation was maintained by a dominant regulatory mechanism that allowed naïve graft-specific T cell activation and proliferation but inhibited their differentiation. Taken together, anti-LFA-1 and anti-CD154 appeared to partially inhibit T cell reactivity without inducing early T cell tolerance. However, long-term graft survival and tolerance generated by these antibodies were maintained by an active regulatory mechanism protecting the graft from naïve T cells. I therefore hypothesize that, instead of immediately generating tolerance upon interaction with responding T cells, antibodies targeting T cell activation signals dampen initial T cell reactivity to allow early transplant survival in an immunologically quiescent microenvironment, which allows the transplant itself to then gradually tolerize graft-specific T cells and generate donor-specific tolerance in a time-dependent manner. In other words, the transplant, and not the therapeutic antibodies, is the key tolerogen for successful generation of tolerance.
Language
English
DOI
doi:10.7939/R3ZG6GJ51
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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