Bone Marrow Transplantation Across Major Genetic Barriers

Contents......Page 10
Preface......Page 8
Introduction......Page 14
Crossing the HLA Barrier in SCID Patients......Page 15
The Experimental Basis for “Megadose” Transplants in Leukemia Patients......Page 16
How “Megadose”Transplants Overcome the Immune Barrier Initial Evidence for Tolerance Induction by Human CD34+ Hematopoietic Progenitor Cells......Page 20
A Major Remaining Challenge: Enhancing Immune Reconstitution......Page 30
References......Page 32
Introduction......Page 42
Overcoming HLA-Histocompatibility Barriers......Page 44
a) Engraftment and GvHD......Page 47
b) Leukemia Relapse......Page 48
c) Non-Leukemic Mortality......Page 51
d) Event-Free Survival......Page 53
Haploidentical SCT Based on Feto-Maternal Microchimaerism......Page 55
Conclusions......Page 56
References......Page 57
Introduction......Page 66
Haplo RIC Using CD3/CD19-depleted Grafts......Page 68
Literature......Page 76
Introduction......Page 80
Establishment of the GIAC Protocol......Page 82
Engraftment......Page 85
Graft-vs-host disease......Page 87
Relapse and management......Page 90
Transplant-related mortality and survival......Page 94
Posttransplant immune reconstitution......Page 96
Simultaneous Induction of T Cell Tolerance in Bone Marrow and Peripheral Blood Grafts by Treating Healthy Donors with G-CSF......Page 98
Maintaining the Hyporesponsiveness of T Cells After in vitro Mixture of G-PB and G-BM in Different Proportions......Page 99
Combination of Immunologic Suppressive Agents......Page 100
Conclusions......Page 101
References......Page 103
Introduction......Page 110
The Immunological Basis of Alloanergization......Page 111
Ex Vivo Alloanergization of Bone Marrow......Page 113
Pharmacological GvHD Prophylaxis and Supportive Care......Page 114
GvHD......Page 115
Immune Reconstitution......Page 116
In Vitro Studies of Efficacy and Specificity of Alloanergization of Human Peripheral Blood Mononuclear Cells......Page 118
Alloanergization Reduced Alloproliferative Responses in both CD4+ and CD8+ Donor T Cells......Page 119
Functional CD4+ and CD8+ T Cell Responses to Human Herpes Viruses Were Retained after Alloanergization......Page 120
Summary......Page 121
Stem Cell Source and Conditioning Regimen......Page 122
Dose Escalation of Alloanergized Donor T Cell Infusion......Page 124
Measurement of Functional Antigen-specific Immune Reconstitution......Page 125
Final Summary......Page 126
References......Page 127
Introduction......Page 132
Evolving Strategies to Overcome HLA Barriers......Page 133
Effective T Cell Depletion: A Pivotal Platform in the Development of Haploidentical/Mismatched Transplantation......Page 134
Early Development in T Cell Depletion......Page 136
Recent Advances in T Cell Depletion......Page 137
Positive CD34 Selection......Page 138
CD3+/CD19+ Depletion......Page 139
In vivo T cell Depletion Using Alemtuzumab or ATG......Page 140
The Rationale of Haploidentical/Mismatched Transplantation Using Nonmyeloablative Conditioning......Page 141
Results from Tuebingen/Dresden......Page 143
Results from Massachusetts General Hospital......Page 147
Results from Osaka University......Page 148
Results from Duke University......Page 149
Harnessing the Beneficial Effects of the Natural Killer Cell /KIR Ligand......Page 151
Harnessing the Beneficial Effects of the Nonfetal Maternal Antigen......Page 153
Selective T Cell Depletion of Allografts......Page 154
Cotransplantation of Mesenchymal Stem Cells......Page 155
Prophylatic/Pre-emptive Donor Lymphocyte Infusion......Page 156
Adoptive Immunotherapy and Vaccination......Page 158
Conclusions......Page 159
References......Page 160
Introduction......Page 176
NK Cell Alloreactivity in Allogeneic Hematopoietic Transplantation: Preclinical Data......Page 178
Donor-Versus-Recipient NK Cell Alloreactivity in Allogeneic Hematopoietic Transplantation......Page 179
Guidelines for NK-Alloreactive Donor Selection......Page 183
References......Page 184
Cytomegalovirus......Page 190
Epstein–Barr Virus......Page 191
Donor Lymphocyte Infusions......Page 192
Depletion of Alloreactive T Cells......Page 193
Enrichment of Antigen-specific T Cells......Page 194
Cytomegalovirus......Page 196
Fungus-specific T Lymphocytes......Page 197
References......Page 198
Introduction......Page 206
Depletion of Alloreactive T Cells......Page 207
Antivirus-Specific Immunotherapy......Page 212
Ex Vivo Expansion of a Human Progenitor Committed to the T Cell Lineage and Able to Seed the Thymus......Page 215
References......Page 219
Introduction......Page 224
Structure of Adenovirus......Page 225
The Role of T Cells in Adenovirus-Specific Immunity......Page 226
Incidence and Risk Factors of Adenovirus Infection Post-HSCT......Page 227
Diagnosis and Surveillance of Adenovirus Infection After Haploidentical Transplantation......Page 230
Clinical Symptoms of Adenovirus Infection Posttransplant......Page 232
Pharmacologic Treatment of Adenovirus Infections Post-HSCT......Page 233
Adoptive T Cell Transfer in Adenovirus Infections Post-HSCT......Page 235
References......Page 237
Introduction......Page 246
Evidence for Immunomodulation by Endogenous Regulatory T Cells in the Murine BMT Models......Page 247
Possible Mechanisms of Regulatory T Cell Control of GvHD......Page 248
Impact of Regulatory T Cells on Antitumor Immunity......Page 251
Calcineurin Inhibitors: Cyclosporine A and Tacrolimus (FK506)......Page 252
Impact of Rapamycin on Treg and Effector T Cells......Page 253
Mycophenolate Mofetil......Page 254
Anti-IL-2 Receptor Antibodies......Page 255
FTY720......Page 256
Isolation and Expansion......Page 257
Clinical Trials......Page 258
Summary and Conclusions......Page 259
References......Page 260
Introduction......Page 270
Fungi and Immunity: An Intriguing Relationship......Page 272
Dendritic Cells Provide Antifungal Immune Resistance......Page 275
Dendritic Cells Induce Protective Tolerance......Page 276
Antifungal Treg Concomitantly Suppress Inflammation and Alloreactivity......Page 277
IDO Contributes to Protective Tolerance......Page 278
Exploiting TLR for Transplantation Tolerance: The Lesson from Thymosin α1......Page 281
Immunotherapeutic Perspectives......Page 283
References......Page 284
Introduction......Page 292
T Cell Depletion......Page 293
HSC Source......Page 294
Recipient Age......Page 295
Immunophenotypic Analysis of T Lymphocytes......Page 296
Immunophenotypic Analysis of B Lymphocytes......Page 298
Antigen-Specific T Lymphocyte Function......Page 299
Antigen-Specific B Lymphocyte Function......Page 301
Attempts to Improve Post-HSCT Immune Reconstitution......Page 302
Keratinocyte Growth Factor......Page 303
Delayed Lymphocyte Infusions......Page 304
Alloreactive-Depleted Donor Lymphocyte Infusions......Page 305
Anergization......Page 306
Haploidentical HSCT......Page 307
References......Page 308
Introduction......Page 316
The Thymic Lymphoid Compartment......Page 318
The Thymic Stromal Compartment......Page 321
Pathways of Posttransplant T Cell Regeneration......Page 323
Thymic-Independent T Cell Regeneration......Page 324
Thymic-dependent T Cell Regeneration:The Phenotype…......Page 325
…and the Quality......Page 327
Limitations on Thymus-dependent T Cell Regeneration......Page 331
Human Thymic Function in the Context of Acute GvHD......Page 332
Pathomechanisms of Thymic Insufficiency:Insights from Preclinical GvHD Models......Page 334
Thymic Dysfunction as a Link to Autoimmunity/Chronic GvHD?......Page 336
Interventions to Improve Immune Regeneration via Protection of Thymic Epithelium by Fibroblast Growth Factor 7......Page 338
References......Page 342
Introduction......Page 364
The Multipotent Hematopoietic Stem Cell and T Cell Potency......Page 367
Human T Cell Differentiation and Development in the Thymus......Page 369
Models for Selection of Human Developing T Cells......Page 372
Positive Selection......Page 373
Negative Selection......Page 374
More or Less Notch Matters......Page 375
Notch and Human NK Cell Development......Page 377
Conclusion and Future Directions......Page 378
References......Page 379
Introduction......Page 386
Identification of an Appropriate Target Antigen......Page 389
TCR Gene Transfer via Transduction Protocols......Page 390
Use of Transduced T Cells for Adoptive T Cell Therapy......Page 392
Limitations and Potential Dangers of Adoptive Therapy Using Transduced T Cells......Page 394
Selection of High-Affinity TCRs......Page 396
Optimising Vectors and TCR Constructs......Page 397
Optimising T Cell Populations Used for Adoptive Transfer......Page 399
Optimizing the Host Environment......Page 401
Conclusions......Page 402
Future Directions......Page 403
References......Page 404
Introduction......Page 410
Minor Histocompatibility Antigens......Page 411
Tissue Distribution of mHags......Page 412
Clinical Relevance of mHags......Page 413
Beneficial Alloreactive T Cell Responses......Page 414
HLA Class II–Restricted T Cell Responses......Page 415
Allo-HLA-Hematopoiesis — Restricted T Cell Responses......Page 416
Adoptive Transfer of Alloreactive T Cells......Page 417
References......Page 419
Introduction......Page 426
G-CSF-induced Mobilization......Page 429
Mobilization Induced by Other Cytokines and Chemokines......Page 430
Mobilization Induced by CXCR4 Antagonists......Page 431
Functional Preclinical Models......Page 432
Adhesion Molecules Keep HSPCs in the Niche......Page 434
Proteases Release HSPCs from their Niches......Page 436
The SDF-1/CXCR4 Axis......Page 437
Bone Remodeling: Osteoblast and Osteoclast Activities Regulate HSPC Behavior......Page 439
The Nervous System Regulates HSPCs and their Niches......Page 441
The Endothelial Cells — Keepers of the Blood–Bone Barrier......Page 442
Future Directions......Page 443
References......Page 444
Introduction......Page 454
The Discovery of IBM-BMT......Page 455
IBM-BMT for Regeneration Therapy......Page 457
IBM-BMT + Donor Lymphocyte Infusion (DLI) for Treatment of Malignant Tumors......Page 459
Novel BMT (PM+IBM-BMT) is Superior to Conventional BMT......Page 460
Acknowledgments......Page 462
References......Page 463
Introduction......Page 470
Tolerance Induction by Allogeneic Hematopoietic Cell Transplantation......Page 471
Experimental Approaches to Achieving Mixed Chimerism......Page 473
Role for Mixed Chimerism in the Treatment of Hematologic Malignancies......Page 476
Convergence of Mixed Chimerism Induction for Tolerance Induction and Treatment of Hematologic Malignancies......Page 478
References......Page 482
Index......Page 490