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

  • Author / Creator
    Wang, Szu-I
  • 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.

  • Subjects / Keywords
  • Graduation date
    2013-11
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R3ZG6GJ51
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Department of Medical Microbiology and Immunology
  • Specialization
    • Immunology
  • Supervisor / co-supervisor and their department(s)
    • Gill, Ronald (Medical Microbiology and Immunology)
    • Anderson, Colin (Medical Microbiology and Immunology)
  • Examining committee members and their departments
    • Rayat, Gina (Medical Microbiology and Immunology)
    • Baldwin, Troy (Medical Microbiology and Immunology)
    • Kane, Kevin (Medical Microbiology and Immunology)
    • Barry, Michele (Medical Microbiology and Immunology)
    • Rothstein, David (University of Pittsburgh, Department of Immunology)