Anti-CD40 Mediated Blockade of the CD40 CostimulatoryPathway Public

Gilson, Christopher Raleigh (2008)

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