Immunomodulation in Transplantation: Promoting Tolerance and Preserving Protective Immunity Open Access

Pinelli, David Francis (2016)

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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

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