Immune Modulatory Strategies to Prevent Costimulation Blockade Resistant Rejection Restricted; Files & ToC

Abstract

Costimulation blockade (CoB) is a promising new transplant immunosuppression strategy offering improved long-term patient and allograft survival without the nephrotoxicity of calcineurin inhibitors. However, increased risks of acute rejection have impeded the widespread adoption of CoB. This dissertation sought to determine how modulating the current CoB regimen in two separate ways could improve transplant survival. By interrupting the type I interferon receptor (IFNAR) signaling during CoB, fully MHC mismatched BALB/c skin grafted onto C57BL/6J mice survived significantly longer than CoB alone. We determined that IFNAR signaling on recipient hematopoietic cells was the primary contributor to rejection during CoB, and that this treatment regimen showed efficacy in a preliminary pilot study in nonhuman primates. In addition, we explored how modifying the costimulation blockade reagent, by using an anti-CD28 domain antibody (dAb), affects skin graft survival and T cell differentiation in the clinically relevant setting of T cell depletion (TCD) and homeostatic reconstitution. By selectively blocking CD28 signaling, CTLA-4 coinhibition can occur, further inhibiting effector T cell responses and enhancing regulatory T cell function. We found that TCD+anti-CD28dAb improved BALB/c to C57BL/6 skin graft survival compared to anti-CD28dAb alone. Furthermore, we observed reduced CD69 expression on CD4⁺ and CD8⁺ T cells in mice that received TCD+anti-CD28dAb compared to TCD alone. In the kidney, the frequencies of tissue resident CD69⁺CD103⁺CD4⁺ T cells were reduced in TCD+CD28dAb compared to TCD alone. We also observed an increased frequency of CD8⁺Foxp3⁺ T cells in the blood and kidney of mice given TCD+anti-CD28dAb compared to TCD alone. These findings demonstrate that blocking IFNAR signaling or changing the CoB regimen to selectively target CD28 signaling could lead to improvements critical for the widespread implementation of CoB in the clinic.

Table of Contents

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About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Medicine and Surgery Health Sciences, Immunology
Palabra Clave	Transplantation Costimulation Blockade
Committee Chair / Thesis Advisor	Andrew Adams, University of Minnesota Mandy Ford, Emory University
Committee Members	Joshy Jacob, Emory University Byron Au-Yeung, Emory University Luisa Cervantes-Barragan, Emory University

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