Transgenesis and Targeted Mutagenesis in Immunology (eBook)

Front Cover 1
Transgenesis and Targeted Mutagenesis in Immunology 4
Copyright Page 5
Table of 
6 
Contributors 14
Preface 20
Chapter 1. Transgenic Mouse Models to Study VDJ Recombination 22
I. Introduction 22
II. Transgenic Model to Define VDJ Recombination Regulatory Elements: Evidence That Recombinational Sequences Are Associated with Lymphoid Transcriptional Enhancers 24
III. Other Transgenic Models 29
IV. Future Prospects 31
V. Concluding Remarks 33
Acknowledgments 33
References 33
Chapter 2. Lymphocyte Development and Function in T Cell Receptor and RAG-1Mutant Mice 36
I. Introduction 36
II. Creation of Mutant Mice 37
III. Thymocyte Development 38
IV. Model for the Role of TCR Genes in aß Thymocyte Differentiation 49
V. Lymphocyte Function 50
Acknowledgments 55
References 55
Chapter 3. RAG-2-Deficient Blastocyst Complementation 56
I. Introduction 56
II. Procedures 57
III. Applications 64
IV. Prospects 67
Acknowledgments 69
References 69
Chapter 4. Role of CD4 and CD8 in Determining Cell Fate in the Thymus 72
I. Background 72
II. Coreceptor Transgenes and TCR Repertoire Selection 74
III. Coreceptor Transgenes and Thymocyte Lineage Commitment 78
IV. Other Data Pertaining to Coreceptor Lineage Commitment 82
V. Future Directions 84
Acknowledgments 85
References 85
Chapter 5. T Cell Development in CD4, CD8, and p56ICK Gene-Targeted Mice 88
I. Introduction 88
II. T Cell Development in CD4, CD8, and CD4 and CD8 Double-Negative Mice 91
III. Thymic Development in p56ICK-Deficient Mice 99
IV. Concluding Remarks 100
References 101
Chapter 6. T Cell Tolerance in T Cell Receptor Transgenic Ipr/lpr Mice 104
I. Introduction 105
II. Effect of T Cell Receptor Transgenes on T Cell Development in Ipr/lpr Mice 105
III. Loss of T Cell Tolerance in Db/HY T Cell Receptor Transgenic Ipr/lpr Mice 116
IV. Loss of T Cell Tolerance in Vß8 T Cell Receptor Transgenic MRL Ipr/lpr Mice Neonatally Tolerized by the Staphylococcal Enterotoxin B 120
V. Costimulatory Signaling in Vß8 T Cell Receptor Transgenic MRL Ipr/lpr Mice Neonatally Tolerized with Staphylococcal Enterotoxin B 127
VI. Summary 129
Acknowledgments 130
References 130
Chapter 7. Thymocyte Selection and Peripheral Tolerance Using the Lymphocytic Choriomeningitis Virus as a Model Antigen 134
I. Introduction 135
II. Positive Selection 135
III. Negative Selection 139
IV. Tolerance to Peripheral Self-Antigens 142
V. Factors That Influence the Induction of Self-Reactivity 147
VI. Prevention of Autoimmune Disease 149
VII. Concluding Remarks 151
Acknowledgments 151
References 151
Chapter 8. Peripheral T Cell Tolerance: Distinct Levels and Multistep Mechanisms 156
I. Introduction 156
II. Thymic Tolerance Induction by Minute Amounts of Antigen 157
III. Parameters Controlling Peripheral Tolerance Induction 158
IV. Distinct Manifestations of Peripheral Tolerance Due to Differential Expression of Self-Antigen 159
V. Influence of the Amount of Antigen Expressed on Peripheral Tolerance Induction 161
VI. Tolerance Induction as a Multistep Process 165
VII. Anergy versus Memory 167
VIII. Summary and Conclusions 167
References 168
Chapter 9. 
170 
I. Introduction 170
II. Class II MHC Transgenic Animals 171
III. INS-HA Transgenic Animals 171
IV. TCR INS-HA Transgenic Animals 172
V. Discussion 173
VI. Conclusions 174
Acknowledgments 175
References 175
Chapter 10. Studies of Tolerance, Inflammation, and Autoimmunity inTransgenic Mice 176
I. Introduction 177
II. TNFa and TNFß Are Sufficient to Induce an Inflammatory Infiltrate but Cannot Induce Autoimmunity 178
III. Antigen Recognition and Its Consequences in SV-40 T Antigen Transgenic Mice 180
IV. Two-Signal Model of T Cell Activation: Role of T Cell Activation in the Induction of Autoimmunity 188
V. Can Locally Produced Interleukin 2 Bypass Tolerance Mechanisms?: Interleukin 2 Expression in Pancreatic B Cells Leads to Insulitis and Diabetes 190
VI. Concluding Remarks 192
Acknowledgments 193
References 193
Chapter 11. Immunological Studies Utilizing Cytokine Transgenic Mice 196
I. Introduction 196
II. Localized Expression of Interferon y 197
III. Expression of Interleukin 10, an Immunoinhibitory Cytokine 199
IV. Expression of Other Cytokines 200
V. Expression of Molecules Other Than Cytokines 201
VI. Conclusion 202
References 202
Chapter 12. Effect of MHC Class II Encoding Transgenes on Autoimmunity in Nonobese Diabetic Mice 204
I. Introduction 204
II. Effect of Transgenic Ea Expression on Insulin-Dependent Diabetes Mellitus 206
III. Effect of Mutated Ab Transgenes on Insulin-Dependent Diabetes Mellitus 208
IV. Conclusion 210
References 210
Chapter 13. Development and Function of the Immune System in Mice with Targeted Disruption of the Interleukin 2 Gene 212
I. Introduction 226
II. Generation of Interleukin 4-Deficient Mice by Targeted Mutagenesis 228
III. Effect of Interleukin 4 on B Cell Development and Differentiation 228
IV. Effect of Interleukin 4 on T Cell Development and Differentiation 235
V. Role of Interleukin 4 in Allergy 240
VI. Outlook 245
Acknowledgments 246
References 246
Chapter 14. Immune Responses in Interleukin 4-Deficient Mice 226
I. Introduction 212
II. Generation of Interleukin 2-Deficient Mice 213
III. Lymphopoiesis and Leukocyte Homeostasis in Young and Adult Mutant Mice 214
IV. Immune Functions in Young Healthy Animals 216
V. Development of Disease and Mortality of Adult Interleukin 2-Deficient Mice 221
VI. Inflammatory Bowel Disease in Interleukin 2-Deficient Mice 221
VII. Concluding Remarks 222
References 223
Chapter 15. Manipulation of Transgene-Encoded Self-Antigens to Explore Mechanisms of B Cell Tolerance 250
I. Introduction 274
II. Anti-CD8 IgM Transgenic Mouse Lines 276
III. Conclusions 284
Acknowledgments 287
References 287
Chapter 16. Transgenic Mouse Model for Peripheral B Cell Tolerance 274
I. Introduction 250
II. Effects of Lysozyme on Self-Reactive B Cells 251
III. B Cell Anergy versus Elimination 256
IV. Physiological and Pathological Implications of B Cell Elimination by Arrested Development 269
References 270
Chapter 17. Immunobiology of MHC Class l-Deficient Mice 290
I. Introduction 290
II. Production of ß2m-Deficient Mice 292
III. Effects of ß2m Deficiency on Cell Surface Expression of Class I Molecules 293
IV. Defective Lymphocyte Development in Class l-Deficient Mice 295
V. Effect of Class I Deficiency on Susceptibility to Natural Killer Cells and Development of Natural Killer Activity 300
VI. Transplantation Studies 302
VII. Responses of Class l-Deficient Mice to Pathogens 306
VIII. Summary and Conclusions 314
Acknowledgments 315
References 315
Chapter 18. 
320 
I. Introduction 320
II. Studies in MHC Class II Mutant Mice 321
III. MHC-Deficient Mice 326
IV. Conclusion 328
Acknowledgments 328
References 328
Index 332