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

Pinelli, David Francis (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/sx61dm98k?locale=en
Published

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

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
School
Department
Subfield / Discipline
Degree
Submission
Language
  • English
Research field
Keyword
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files