Immunomodulation in Transplantation: Promoting Tolerance and Preserving Protective Immunity Open Access
Pinelli, David Francis (2016)
Abstract
Transplantation is a widely accepted treatment for many end-stage organ diseases. However, current post-transplant immunomodulatory regimens are extremely toxic and non-specific, which limits long-term graft survival and leaves patients susceptible to opportunistic infections. Costimulation blockade (CoB) with monoclonal antibodies is a novel treatment modality aimed at preventing the activation and proliferation of alloreactive T lymphocytes. While CoB better targets graft-reactive immune responses and offers a reduced toxicity profile compared to current standard of care drugs, several barriers remain that limit the widespread adoption of CoB in transplantation. Our studies aimed to refine the balancing act of immunomodulation following transplantation, in order to promote the tolerance of a foreign organ while simultaneously maintaining protective, pathogen-specific immune responses and limiting off-target side effects. Patients receiving belatacept, a novel CTLA4-Ig fusion protein that blocks CD28-mediated costimulation, often experience lymphoproliferative complications following primary infection with Epstein-Barr Virus. Rapamycin, an anti-fungal macrolide used for decades in transplantation to inhibit graft-specific T cell proliferation, has recently been shown to paradoxically enhance CD8+ T cell responses to pathogen infection. We utilized a clinically-relevant murine model to demonstrate that rapamycin was able to enhance the quantity and quality of CD8+ T cell responses to gammaherpesvirus infection in the presence of CTLA4-Ig. This augmented immune response reduced viral burden in infected animals, suggesting that this treatment may be able to improve patient outcomes and limit infectious complications. We also investigated the use of CoB targeting the CD40-CD154 costimulatory pathway, which is involved in many highly immunogenic processes. While anti-CD154 antibodies showed great promise in preclinical studies, thromboembolic complications during clinical trials, due to interactions of the Fc portion of antibody molecules with platelet-expressed Fc receptors, stymied the translation of this therapy. We tested a novel Fc-silent anti-CD154 domain antibody, and found that this modified reagent was equally efficacious at prolonging graft survival and limiting alloreactive T cell responses compared to Fc-intact therapy. These findings provide proof-of-concept that safe, efficacious CoB therapeutic regimens may be developed to aid in the promotion of tolerance in graft recipients and reduce morbidity and mortality in this vulnerable population.
Table of Contents
Chapter 1. Introduction
History of Clinical Transplantation 2
The Origins of Immunosuppressive Therapy 4
Costimulation Blockade 6
The CD40 Costimulatory Pathway 9
The Inhibitory Fc Receptor FcγRIIB 13
The Importance of Treg for Transplant Tolerance 14
Heterologous Immunity and Alloantigen-Specific Memory T Cells 19
Post-Transplant Opportunistic Infection and Morbidity 21
mTOR Inhibition in Transplantation 24
Rapamycin-Induced Augmented T Cell Immunity 25
CD8+ T Cell Metabolism and Cell Fate 28
Conclusions 29
References 30
Chapter 2. An Anti-CD154 Domain Antibody Prolongs Graft Survival and Induces FoxP3+ iTreg in the Absence and Presence of CTLA-4 Ig
Abstract 58
Introduction 59
Materials and Methods 61
Results 64
Discussion 69
Figures and Figure Legends 71
References 85
Chapter 3. The Inhibitory FcγRIIB Functionally Inhibits Donor-Reactive Memory CD8+ T Cell Responses Following Transplantation
Abstract 90
Introduction 91
Materials and Methods 94
Results 96
Discussion 100
Figures and Figure Legends 103
References 113
Chapter 4. Rapamycin Ameliorates the CTLA4-Ig-Mediated Defect in the CD8+ T Cell Response to Gammaherpesvirus Infection
Abstract 119
Introduction 120
Materials and Methods 123
Results 125
Discussion 129
Figures and Figure Legends 133
References 149
Chapter 5. Discussion
Discussion 155
Figures and Figure Legends 168
References 172
About this Dissertation
| School | |
|---|---|
| Department | |
| Degree | |
| Submission | |
| Language |
|
| Research Field | |
| Keyword | |
| Committee Chair / Thesis Advisor | |
| Committee Members |
Primary PDF
| Thumbnail | Title | Date Uploaded | Actions |
|---|---|---|---|
|
|
Immunomodulation in Transplantation: Promoting Tolerance and Preserving Protective Immunity () | 2018-08-28 14:38:34 -0400 |
|
Supplemental Files
| Thumbnail | Title | Date Uploaded | Actions |
|---|