Anti-CD40 Mediated Blockade of the CD40 Costimulatory Pathway Open Access

Gilson, Christopher Raleigh (2008)

Permanent URL: https://etd.library.emory.edu/concern/etds/rf55z792v?locale=en
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Abstract


Abstract
Anti-CD40 Mediated Blockade of the CD40 Costimulatory Pathway
By Christopher Raleigh Gilson

Transplantation is often the sole therapy available for many forms of end-stage organ
disease. The field of transplantation owes much of its success to the development of
immunosuppressive drugs which predominantly seek to inhibit the T cell-dependent
process of rejection. Due to the inherent disadvantages of non-specific
immunosuppression, considerable interest has been place in developing more selective
strategies. Transient blockade of the CD40 pathway, in conjunction with CD28
blockade, has shown great promise in tolerance induction protocols to inactivate of donor
reactive T cells. However, anti-CD154 monoclonal antibodies that have for years been
the foundation of these approaches also cause thromboembolism in humans. The central
hypothesis of this thesis is that blockade of the CD40 signaling pathway through the use
of anti-CD154 or anti-CD40 monoclonal antibodies can equally promote chimerism and
graft survival. The functional equivalence between these two approaches highlights the
importance of inhibiting the CD40 pathway itself.



Table of Contents
Chapter 1: Introduction

Significance for the Study of Transplantation
2
A
Brief
Historical
Context
3
T cell Activation
6
The
CD28
Signaling
Pathway
7
The
CD40
Signaling
Pathway
8
Clinical
Methods
of
Immunosuppression
10
Development of and Prospects for Costimulatory
Blockade
12
Conclusions
15
Chapter 2: Equivalent Efficacy Between Anti-CD40 and Anti-CD154
Antibodies in Costimulation Blockade
Abstract
18
Introduction
19
Methods 21
Results
24
Discussion
29
Figure
Legends 32
Chapter 3: Divergent Functions of IgG1 and IgG2b Anti-CD40 Antibody
Isotypes in Blockade of the CD40 Costimulatory Pathway

Abstract
42
Introduction
43
Methods
46
Results
51
Discussion
62
Figure
Legends
65


Table of Contents

Table of Contents

Chapter 1: Introduction
Significance for the Study of Transplantation 2
A Brief Historical Context 3
T cell Activation 6
The CD28 Signaling Pathway 7
The CD40 Signaling Pathway 8
Clinical Methods of Immunosuppression 10
Development of and Prospects for Costimulatory Blockade 12
Conclusions 15

Chapter 2: Equivalent Efficacy Between Anti-CD40 and Anti-CD154 Antibodies in Costimulation Blockade
Abstract 18
Introduction 19
Methods 21
Results 24
Discussion 29
Figure Legends 32

Chapter 3: Divergent Functions of IgG1 and IgG2b Anti-CD40 Antibody Isotypes in Blockade of the CD40 Costimulatory Pathway
Abstract 42
Introduction 43
Methods 46
Results 51
Discussion 62
Figure Legends 65

Chapter 4: Discussion
Introduction 85
Blockade of the CD40 Signaling Pathway: Optimistic Consternation 86
Therapeutic Targets Down-Stream of the CD40 Pathway 88
On the Role of Antibody Isotype 89
General Conclusions 92
Epilogue 94

References 95

















List of Figures

Chapter 2
Figure 2.1 35
Figure 2.2 36
Figure 2.3a 37
Figure 2.3b 38
Figure 2.4 39
Figure 2.5 40

Chapter 3
Figure 3.1 71
Figure 3.2 72
Figure 3.3 73
Figure 3.4 74
Figure 3.5a 75
Figure 3.5b 76
Figure 3.5c 77
Figure 3.6 78
Figure 3.7a 79
Figure 3.7b 80
Figure 3.8 81
Figure 3.9 82
Figure 3.10 83

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