Contents

1. Genes, Transcripts and Proteins of CD137 Receptor and Ligand 1

Dass S. Vinay and Byoung S. Kwon

1. Overview 1

2. Discovery, Alternative Names, and Structure of CD137 3

3. The CD137 Gene 4

4. The CD137 Protein 5

5. CD137L 6

5.1. The Discovery of CD137L 6

5.2. CD137L Structure and Expression 6

6. CD137L Gene 7

7. CD137L Protein 7

7.1. Regulation of RNA and Protein Expression 8

7.2. CD137-CD137L in Health and Disease 9

8. Future Directions 11

Acknowledgments 11

References 11

2. CD137 Signal Transduction 15

Hyeon-Woo Lee and Byoung S. Kwon

1. Background 15

2. CD137(4-1BB) As an Immune Stimulator 16

3. CD137 Signal Transduction 17

4. Concluding Remarks 22

References 23

3. Significance of Reverse Signal Transduction for the

Biology of the CD137 Receptor/Ligand System 29

Herbert Schwarz

1. Biology of Reverse Signaling Through CD137 Ligand 30

1.1. CD137 Ligand Activities on Monocytes and Macrophages 30

1.2. CD137 Ligand Activities on Dendritic Cells 34

1.3. CD137 Ligand Activities on B Cells 34

1.4. CD137 Ligand Activities on Bone Marrow Cells 35

1.5. CD137 Ligand Activities on T Cells 36

1.6. CD137 Ligand Activities on Non-hematopoietic Cells 37

1.7. CD137 Ligand Signal Transduction Pathway 39

1.8. Regulation of CD137 Ligand Signaling 39

1.9. Influence of Soluble CD137 and Soluble CD137 Ligand on

CD137 Ligand Signaling 39

2. Bidirectional Signaling in Other Receptor/Ligand Systems 40

3. Concluding Remarks 41

References 42

4. CD137 Signal in the Regulation of Innate Immunity 47

Lieping Chen

1. Introduction 47

2. NK Cells 47

3. Macrophages/Monocyte 49

4. Dendritic Cells 50

5. Granulocytes 51

6. Summary 52

References 52

5. Regulation of T Cell-Dependent Humoral Immunity

Through CD137 (4-1BB) Mediated Signals 55

Robert S. Mittler, Liguo Niu, Becker Hewes, and Juergen Foell

1. Introduction 56

2. T and B Cell Activation and Costimulation 56

3. CD137 Expression and T Cell Costimulation 59

4. Anti-CD137-Mediated Suppression of Humoral Immunity 60

5. Anti-CD137 Induced Suppression of Autoantibodies 64

6. DC Function, CD137 Expression and Signaling 69

7. Anti-tumor Immunity and B Cells 72

8. Anti-CD137 mAbs Disrupt Hematopoiesis in Mice 74

9. Concluding Remarks 77

References 77

6. CD137 in the Regulation of T Cell Response to Antigen 83

Yuwen Zhu and Lieping Chen

1. CD137 in Naive T Cell Costimulation 83

1.1. Effects of CD137 Engagement on CD8+ T Cells 83

1.2. Effects of CD137 on CD8+ T Cell Priming, Division and Survival 85

1.3. Effects of CD137 on CD4+ T Cells: Positive or Negative? 86

2. CD137 and Regulatory T Cells (Treg) 87

3. CD137 and T Cell Anergy 88

4. CD137 and Memory T Cell (Tm) Response 90

5. Conclusions and Perspectives 92

References 92

7. Autoimmune Diseases 97

Yonglian Sun and Yang-Xin Fu

1. Introduction 97

2. Role of CD137/CD137L Interaction in the Pathogenesis of Autoimmune Diseases 98

2.1. Lack of CD137/CD137L Interaction Prevents Autoimmune Diseases 98

2.2. Soluble CD137 and Autoimmune Diseases 99

3. Treatment of Autoimmune Disease with Agonistic Anti-CD137 100

3.1. Experimental Autoimmune Encephalomyelitis (EAE) 101

3.2. Experimental Autoimmune Uveitis (EAU) 102

3.3. Systemic Lupus Erythematosus (SLE) 103

3.4. Collagen-induced Arthritis (CIA) 105

3.5. Chronic Graft-Versus-Host Disease (cGVHD) 105

4. Mechanisms Involved in CD137 Agonist-mediated Inhibition of Autoimmune Diseases 106

4.1. Apoptosis of T Lymphocytes 106

4.2. Regulatory T Cells and IFN-y 107

4.3. Helper T Cell Anergy 108

4.4. B Cell Apoptosis 109

5. Summary 109

References 110

8. CD137/CD137 Ligand in Tumor and Viral Immunotherapy 117

Ignacio Melero, Oihana Murillo, Inigo Tirapu, Eduardo Huarte, Ainhoa Arina, Laura Arribillaga, and Juan Jose Lasarte

1. CD137 (4-1BB) and CD137 Ligand (4-1BB-Ligand) Meet Tumor

Immunology 117

1.1. The Arrival of Agonistic Anti-CD137 Monoclonal Antibodies 117

1.2. A Comparison with Anti-CTLA-4 Monoclonal Antibodies 118

1.3. Transfection of CD137 Ligand into Malignant Cells 120

2. Developments and Improvements on CD137/CD137 Ligand Therapeutic Strategies 121

2.1. Immunization: CD137 Breaks Ignorance and Tolerance 121

2.2. CD137 as an Adjuvant for Adoptive T Cell Therapy and Bone Marrow Transplantation 122

2.3. CD137 Acting in Synergy with Cytokines and Other Costimulatory Molecules 124

3. CD137/CD137 Ligand in the Antiviral Immune Response and in Viral Vaccination 126

4. Reflections on the Mechanism(s) of Action 127

5. Using Preclinical Information for Clinical Development of Immunotherapy 128

References 130

Index

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