| Preface | ix |
1. | Structure Prediction and Binding Site Identification of the CD28 and B7 Family Molecules | 1 |
| Abstract | 1 |
| The CD28 and B7 Families: Mediators of T Cell Costimulation | 1 |
| The CD28 and B7 Families and the Immunoglobulin Superfamily | 2 |
| Sequences, Topology and Binding Characteristics | 2 |
| Structure-Function Analysis Based on Comparative Protein Models and Mutagenesis | 4 |
| Comparative Modeling of IgSF Proteins Sharing Low Sequence Similarity | 5 |
| Molecular Models of CTLA-4 and CD80/CD86 | 6 |
| Mapping of Binding Sites | 7 |
| Experimentally Determined Structures | 8 |
| Evaluation of Predictions | 9 |
| Conclusions | 9 |
2. | T Lymphocyte Signaling Pathways Regulated by CD28 and CTLA-4 | 12 |
| Introduction | 12 |
| CD28 Costimulation | 13 |
| CTLA-4 Signaling | 23 |
3. | Costimulatory Molecules in T Cell Development, Activation and Effector Function: Similar Activity, Opposite Consequences | 38 |
| Abstract | 38 |
| Conceptual Evolution and Molecular Basis of the Second Signal for T Cell Activation | 38 |
| Multiplicity of Costimulatory Molecules | 39 |
| Expanding the Horizon of T Cell Costimulation: From Activation to Effector Function | 39 |
| Costimulatory Molecules in T Cell Development | 40 |
| Negative Costimulation? Paradigm Revisited | 42 |
| B71/2 Mediated Costimulation in T Cell Activation and Development: Similar Activity, Opposite Consequences | 42 |
4. | Negative Costimulatory Functions of B7-H1 | 48 |
| Introduction | 48 |
| Molecular Structure and Expression of B7-H1 | 48 |
| Counter-Receptor of B7-H1 | 50 |
| Immunological Functions of B7-H1 | 51 |
| Effect of Tumor-Associated B7-H1 in Immune Evasion | 52 |
| Reverse Signaling of B7-H1 to Regulate T Cell Responses | 54 |
| Conclusion | 55 |
5. | PD-1:PD-1 Ligand Pathway | 59 |
| Introduction | 59 |
| Structure and Expression of the PD-1 Receptor | 59 |
| Function of PD-1 | 60 |
| Biochemistry Basis for PD-1 Function | 61 |
| Structure and Expression of PD-1 Ligands | 62 |
| Function of PD-1 Ligands | 63 |
| Summary and Concluding Remarks | 65 |
6. | The ICOS/B7RP-1 Costimulation Pathway | 67 |
| Abstract | 67 |
| Introduction | 67 |
| Terminology | 68 |
| Structures of ICOS and B7RP-1 | 68 |
| ICOS Expression | 69 |
| B7RP-1 Expression | 69 |
| Cytokine Regulation by ICOS/B7RP-1 | 70 |
| Immunoglobulin Regulation by ICOS/B7RP-1 | 72 |
| CD28 and CTLA-4 Regulate, but Are Not Required for, ICOS Function | 72 |
| The HpH4 HIV Antigen Is ICOS | 72 |
| ICOS and Apoptosis | 73 |
| B7RP-1-Fc and B7.2-Fc Transgenic Mice Exhibit Intestinal Inflammation | 73 |
| ICOS/B7RP-1 Therapeutic Modalities | 74 |
| Anti-Tumor Activities of B7RP-1 | 74 |
| ICOS Blockade in Transplantation | 75 |
| ICOS Regulation of Secondary and Recall Responses | 75 |
| EAE Studies Reveal the Promise and the Complexity of ICOS/B7RP-1 Regulation | 76 |
| Differential ICOS/B7RP-1 Regulation | 77 |
| Summary | 77 |
7. | Role of ICOS in T Cell Activation | 82 |
| Introduction | 82 |
| Defective T Cell Help for Isotype Class Switching in ICOS Deficient Mice | 82 |
| Identification of a Novel ICOS Ligand Related to CD80 | 84 |
| Role of ICOS in CD4 T Cell Activation | 84 |
| ICOS Costimulation of CD8 T Cells | 87 |
8. | B7-H3 | 91 |
| Introduction | 91 |
| Molecular and in Silico Cloning of B7-H3 | 91 |
| Isoforms of Human B7-H3 | 92 |
| B7-H3 Gene Analysis | 93 |
| B7-H3 Tissue Distribution and Expression of B7-H3R on Activated T Cells | 94 |
| B7-H3 Costimulates T Cell Growth in Vitro | 96 |
| B7-H3 Selectively Increases IFN-[gamma] Production | 97 |
9. | The Role of B7s in Transplantation | 100 |
| Introduction | 100 |
| The Absence of B7 Costimulation Renders T Cells Anergic in Vitro | 100 |
| Blockade of B7 Molecules Prolongs Organ Graft Survival | 101 |
| Allorecognition Pathways Affected by B7 Costimulation | 101 |
| The Role of B7 Molecules in Chronic Graft Rejection | 102 |
| Role of B7 in Xenotransplantation | 102 |
| The Role of B7-1 versus B7-2 Mediated Costimulation in Transplantation Responses | 104 |
| Combination Approaches to Improve Allograft Survival Based upon B7:CD28/CTLA-4 Blockade | 104 |
| CTLA4 Signaling Prolongs Graft Survival | 105 |
| B7 and CD28 Homologues | 106 |
| Overview of ex Vivo Blockade of the CD28/CTLA-4:B7 Pathway for Graft-versus-Host Disease (GVHD) Prevention | 106 |
| Ex Vivo Blockade of B7:CD28/CTLA-4 Interactions in Human Mixed Lymphocyte Reaction (MLR) Cultures | 107 |
| Human Clinical Trial of ex Vivo B7:CD28/CTLA4 Blockade for GVHD Prevention | 107 |
| Adjuvants to B7 Blockade | 108 |
| Modifications of ex Vivo B7:CD28/CTLA4 Costimulatory Pathway Blockade of Human MLR Cultures Designed to Improve the Efficacy of Tolerization | 109 |
| Ex Vivo Tolerization of Murine MLR Cultures by Costimulatory Pathway Blockade As a Means of Achieving GVHD Prevention | 109 |
| In Vivo Blockade of B7:CD28/CTLA4 for GVHD Prevention | 110 |
| Mechanism(s) of GVHD Inhibition by B7:CD28/CTLA-4 Blockade | 111 |
| Role of CD28/CTLA-4:B7 in Graft-versus-Leukemia (GVL) | 112 |
| Role of CD28/CTLA-4:B7 in Alloengraftment | 112 |
| Future Directions | 113 |
10. | B7 Family of Costimulatory Molecules in the Induction and Regulation of Autoimmunity | 118 |
| Introduction | 118 |
| EAE and IDDM | 119 |
| Manipulation of B7 Costimulatory Pathway | 120 |
| Blocking Negative Costimulatory Signals in Autoimmune Diseases | 122 |
| ICOS-B7h Costimulation in Autoimmune Diseases | 123 |
| PD-1:PD-L1/PD-L2 Pathway and Autoimmunity | 124 |
11. | Operation Enduring Costimulation: Modulation of B7 Receptors to Elicit Anti-Tumor Immunity | 128 |
| Turning Up the Offensive | 128 |
| An Alliance of Mediators | 130 |
| Shutting Down the Defense | 131 |
| The New Breed | 133 |
| Future Battles | 134 |
| Index | 139 |