Transplantation of Composite Tissue Allografts (eBook)

Foreword: The Import of Composite Tissue Transplantation 6
Preface 7
Contents 8
Contributors 12
Section I 18
The Establishment of Composite Tissue Allotransplantion as a Clinical Reality 19
1.1 Introduction 19
The Evolution of Composite Tissue Allotransplantation: the Twentieth Century Realization of “ Cosmas and Damian” 29
2.1 Historical Background 29
2.2 Current Status 33
2.2.1 Trachea 34
2.2.2 Peripheral Nerve 34
2.2.3 Flexor Tendon Apparatus 35
2.2.4 Vascularized Knee 35
2.2.5 Lower Extremity 36
2.2.6 Larynx 36
2.2.7 Abdominal Wall 36
2.2.8 Partial Face 37
2.2.9 Complete Face/Scalp 37
References 38
The Impact of the Discovery of Cyclosporine on Transplantation of Composite Tissue Allografts 42
3.1 Introduction 42
3.2 History of Composite Transplantation 42
3.3 Immunosuppression 43
3.4 Cyclosporine: Discovery and Structure 44
3.5 Cyclosporine: Mechanism of Action 46
3.6 Biologic Effects of Cyclosporine 46
References 48
The First Limb Transplants with Cyclosporine 52
4.1 Introduction 52
4.2 The Questions 52
4.3 Materials and Methods 53
4.4 Cyclosporine and Limb Transplants 54
4.5 The Return of Cosmas and Damian 54
References 55
Section II 56
Translational Research in Composite Tissue Allotransplantation 57
5.1 Introduction 57
5.2 Classification of Human Skin Rejection in CTA 58
5.3 Development of a Nonhuman Primate Model for the Study of CTA 60
5.3.1 Postoperative Management 62
5.3.2 Results 64
5.4 Conclusions 65
References 67
Relative Antigenicity of Allograft Components and Differential Rejection 69
6.1 Introduction 69
6.2 Components of Vascularized Tissue Allograft 70
6.2.1 Skin 71
6.2.2 Muscle 74
6.2.3 Tendon 74
6.2.4 Cartilage 75
6.2.5 Bone 75
6.2.6 Nerve 77
6.2.7 Vessels 77
6.3 Discussion 78
References 80
On the Road to Tolerance Induction in Composite Tissue Allotransplantation 84
7.1 Introduction 84
7.2 T-Cell Tolerance 86
7.3 Regulatory T Cells 87
7.4 T Suppressor Cells 88
7.5 Pharmacologic Induction Strategies 89
7.6 Costimulation Blockade 89
7.7 Donor-Specific Transfusions 91
7.8 T-Cell Activation 91
7.9 Dendritic Cells 92
7.10 Microchimerism 94
7.11 Mixed Chimerism 94
7.12 Conclusion 95
References 96
Donor-Specific Tolerance 102
8.1 Introduction 102
8.2 Physiologic Mechanisms of Induction Therapy 103
8.2.1 T Cells 103
8.3 Generation of T Regulatory Cells 104
8.4 T-Cell Costimulatory Blockade 106
8.5 Donor-Specific Transfusion 108
8.6 Gene Therapy for Tolerance Induction 109
8.6.1 Gene Therapy Vectors 110
8.6.2 Chemokine Antagonists 111
8.6.3 MHC Molecules 112
8.6.4 Immunosuppressive Cytokines 112
8.6.5 Blockage of Costimulatory Signals 113
8.7 Conclusion 114
References 114
Immune Tolerance Induction: Basic Concepts for Composite Tissue Allotransplantation 119
9.1 The Clinical Problem and Possible Solution 119
9.2 Immune Tolerance Definition 120
9.3 Immune Mechanisms Implicated in Tolerance 121
9.3.1 Central Tolerance 121
9.3.2 Peripheral Tolerance 122
9.4 Composite Tissue Allograft Rejection 125
9.5 Strategies for Tolerance Induction in CTA 126
References 128
Section III 132
Allograft Survival with Calcineurin Inhibitors 133
10.1 Introduction 133
10.2 Molecular Action of Calcineurin Inhibitors 133
10.2.1 Immunosuppression with Calcineurin Inhibitors and Survival of Composite Tissue Allografts in Small Animals 134
10.2.2 Immunosuppression with Calcineurin Inhibitors and Survival of Composite Tissue Allografts in Large Animals 142
10.2.3 Clinical Applications of Composite Tissue Transplantation and Immunosuppression with Calcineurin Inhibitors 145
10.2.4 Short-Term Immunosuppression with Calcineurin Inhibitors and Tolerance Induction in Composite Tissue Allografts 145
10.3 Future Solutions 156
References 156
Long-Term Prevention of Rejection and Combination Drug Therapy 162
11.1 Introduction 162
11.2 Combination Drug Therapy 162
11.3 First Clinical Applications 165
11.4 Hand Transplantation 167
11.5 Chronic Rejection 169
References 171
Locoregional Immunosuppression in Composite Tissue Allografting 176
12.1 Introduction 176
12.2 Local Immunosuppression 177
12.3 Topical Therapy 178
12.4 IA Infusion 180
12.5 Conclusion 181
References 181
New Approaches to Antibody Therapy 184
13.1 Historical Perspective 184
13.1.1 Immunosuppression 185
13.1.2 Immunomodulation 185
13.2 Antibodies in CTA 186
13.2.1 What are Antibodies? 186
13.2.2 Which Antibodies are Useful in Transplantation? 186
13.2.3 Monoclonal Versus Polyclonal 187
13.2.4 Clinical Use of Antibodies 187
13.3 Antibody-Based Immunosuppressive Agents: Mechanism of Action, Clinical Efficacy, and Safety Profiles 189
13.3.1 Polyclonal Antibodies 189
13.3.2 Monoclonal Antibodies 190
13.3.3 Anti-CD3 Antibody (Muromonab-CD3) 190
13.3.4 Anti-CD25 Antibodies (Basiliximab, Daclizumab): IL-2 Receptor- Directed Antibodies 191
13.3.5 Anti-CD52 Antibody (CAMPATH-1H Alemtuzumab)
13.3.6 Anti-CD20 Antibody (Rituximab) 193
13.3.7 Costimulation Blockade (CD40-CD154 CD28-CD80/ CD86 and CTLA- 4)
13.4 Conclusion 196
References 197
Section IV 203
World Experience of Hand Transplantation- Independent Assessment 204
14.1 Introduction 204
14.2 Recipients 205
14.3 USA (Transplants 1999 and 2001) 207
14.4 Belgium (Transplant 2002) 209
14.5 Austria (Transplants 2000 and 2003) 209
14.6 China (Transplants 1999, 1999, and 2000) 212
14.7 France (Transplants 2000 and 2003) 215
14.8 Italy (Transplants 2000, 2001, and 2002) 217
14.9 Conclusions 217
References 219
Hand Transplantation: Lyon Experience 220
15.1 Introduction 220
References 224
Hand Transplantation: The Louisville Experience 226
16.1 Evolution of the Louisville Hand Transplant Program 226
16.2 Patient profiles 227
16.2.1 Patient 1 227
16.2.2 Patient 2 227
16.2.3 Patient 3 227
16.3 Scientific Rationale for the Louisville Experiment 227
16.4 Ethical Considerations 228
16.5 Recipient and Donor Selection 229
16.6 Recipient Recruitment 231
16.6.1 Medical Screening of Potential Recipients 231
16.6.2 Psychiatric Evaluation 232
16.6.3 Assessment of Insurance Coverage 232
16.6.4 Informed Consent 232
16.7 Donor Procurement 233
16.8 Operative Procedure 233
16.9 Immunosuppressive Regimen 234
16.9.1 Induction Immunosuppression 234
16.9.2 Maintenance Immunosuppression 234
16.10 Posttransplant Rehabilitation 235
16.11 Assessment of Outcomes 236
16.11.1 Functional Evaluation 236
16.11.2 Assessment for Rejection, Graft Versus Host Disease and Immunomonitoring 237
16.11.3 Psychosocial Evaluation 237
16.12 Summary of Outcomes in the American Patients 237
16.12.1 Allograft Survival 237
16.12.2 Function 238
16.12.3 Acute Rejection, Chronic Rejection, GVHD, and Immunomonitoring 239
16.12.4 Psychosocial Status 240
16.13 Complications 240
16.13.1 Patient 1 240
16.13.2 Patient 2 241
16.14 Conclusion 241
References 242
Hand Transplantation: The Innsbruck Experience 245
17.1 Introduction 245
17.2 Inclusion/Exclusion Criteria 245
17.3 Pretransplant Evaluations 246
17.4 Recipients 247
17.5 Donors and Surgery 247
17.6 Rehabilitation 248
17.7 Immunosuppression and Infection Prophylaxis 249
17.8 Results 249
17.8.1 Surgery 249
17.8.2 Infection 250
17.8.3 Immunosuppression and Rejection 250
17.8.4 Chimerism 252
17.8.5 Function 253
17.8.6 Imagery 255
17.8.7 Patient Satisfaction 255
17.9 What’s Important and What’s Not 256
17.10 Conclusion 259
References 259
Section V 262
Vascularized Bone Marrow Transplantation 263
18.1 Introduction 263
18.1.1 The Chimera 263
18.1.2 Tolerance 263
18.1.3 Composite Tissue Transplant 264
18.1.4 Vascularized Bone Marrow Transplant 264
18.2 Chimerism and Tolerance 265
18.2.1 Is the Establishment of Chimerism a Prerequisite to Tolerance? 265
18.2.2 The Stromal Cell 269
18.3 Vascularized Bone Marrow Transplant Models 270
18.3.1 Hindlimb 270
18.3.2 Sternum 273
18.3.3 Femur 275
18.3.4 Procedure for Graft Harvest 275
18.4 Future Studies 277
References 278
Vascularized Bone Marrow Transplantation: Pathology of Composite Tissue Transplantation- Induced Graft- Versus- Host- Disease 282
19.1 Background 282
19.2 Gross Clinical Aspects of VBMT 283
19.3 Acute and Chronic GVHD 284
19.4 Histopathology 284
19.4.1 Skin 284
19.4.2 Liver 285
19.4.3 Gastro-Intestinal Tract 285
19.4.4 Other Tissues 285
19.5 Conclusion 286
References 286
Immune Cell Redistribution After Vascularized Bone Marrow Transplantation 288
20.1 Introduction 288
20.2 Distribution of Donor BMC in Recipient Tissues 289
20.2.1 Distribution of BMC Released from il-BMTx in Syngeneic Recipient 289
20.2.2 The Effect of In Limb-Bone Marrow Transplantation on the Syngeneic Nonirradiated Recipient BM and ( LO) Cellularity 290
20.2.3 The Effect of il-BMCTx on the Syngeneic Irradiated Recipient BM and LO Cellularity 291
20.3 In Vitro Responsiveness of BM Lymphocytes in il- BMTx Recipients 292
20.4 In Vitro Responsiveness of MLN Lymphocyte in il- BMTx Recipients 292
20.5 Histology of Recipient LO Repopulated by il-BMTx 292
20.6 Peripheral Blood Cell Subsets 293
20.7 Distribution of BMC Released from il-BMTx in Allogeneic Recipient 294
20.7.1 Phenotypes of BMC Populating Allogeneic Recipient BM After il- BMTx 295
20.8 Microchimerism in Allogeneic il-BMTx in Immunosuppressed Recipient 296
20.9 Donor DNA Distribution (Noncellular Microchimerism) in Allogeneic il- BMTx Nonimmunosuppressed and Immunosuppressed Recipients 297
20.10 Conclusions 298
References 298
Section VI 300
Vascularized Knee Transplantation 301
21.1 Introduction and History 301
21.2 Indication 301
21.3 Trauma Management 302
21.3.1 Eradication of Infection and Soft Tissue Coverage 302
21.3.2 Preparation for Transplantation 302
21.4 Transplantation 302
21.4.1 Bone Allograft Procurent 302
21.4.2 Back-Table Allograft Preparation 304
21.4.3 Transplantation Procedure 304
21.4.4 Histocompatibility and Immunosuppression 305
21.5 Follow-Up 305
21.6 Results 306
21.6.1 Patient 1 306
21.6.2 Patient 2 306
21.6.3 Patient 3 307
21.6.4 Patient 4 307
21.6.5 Patient 5 307
21.6.6 Patient 6 308
21.7 Discussion and Overview 309
21.7.1 Recurrence of Infection 310
21.7.2 Late Rejection 310
21.8 Summary 313
References 313
Tracheal Transplantation 315
22.1 Introduction 315
22.2 History 316
22.3 Anatomy of the Trachea 317
22.4 Histology of the Trachea 318
22.5 Immunological Aspects of Tracheal Transplantation 318
22.5.1 Tracheal Graft Reepithelialization 319
22.5.2 Desquamation Methods 320
22.5.3 Immunosuppressive Therapy 321
22.5.4 T-Cell Tolerance 322
22.6 Graft Revascularization Techniques 323
22.6.1 Direct Revascularization Techniques 323
22.6.2 Indirect Revascularization Techniques 327
22.7 Human Experience 329
22.7.1 Transplantation of a Cadaveric Human Homograft 329
22.7.2 Free Tracheal Autograft Transplantation 332
22.8 Conclusion 333
References 333
Laryngeal Transplantation 338
23.1 History 338
23.2 The Human Laryngeal Transplant 338
23.3 Animal Models of Laryngeal Transplantation 340
23.4 Reinnervation Research in Laryngeal Transplantation 347
23.5 Future Investigations 348
23.6 Conclusions 349
References 350
Face Transplantation 352
24.1 Introduction 352
24.2 Experimental Facial Transplantation 352
24.3 Preparation for Human Transplantation 355
24.4 Future Approaches 361
References 361
The Role of Allografts in Lower Extremity Reconstruction 363
25.1 History 363
25.2 Etiology of Lower Extremity Wounds 364
25.3 Management of Lower Extremity Wounds 364
25.3.1 Gustilo Classification of Open Fractures of the Tibia 365
25.3.2 Bone Reconstructive Techniques 366
25.4 Soft Tissue Reconstruction 366
25.4.1 Local Flaps Versus Microvascular Tissue Transfers 366
25.5 Composite Tissue Allotransplantation 368
References 372
Skin Allografts in Scalp Reconstruction 375
26.1 Introduction 375
26.2 Anatomy of the Scalp 376
26.3 Current Approaches to Scalp Reconstruction 376
26.4 Scalp Transplantation 380
References 380
Abdominal Wall Transplantation 382
27.1 Introduction 382
27.2 The Abdominal Wall Graft 382
27.3 Intestinal Transplantation 383
27.4 Graft Procurement 384
27.5 Implantation 385
27.6 Timing 386
27.7 Immunosuppression/Rejection 386
27.8 Ethical Considerations 387
References 389
Peripheral Nerve Allotransplantation 390
28.1 Background and Historical Perspectives 390
28.2 Nerve Regeneration 391
28.2.1 Axonal Regeneration 391
28.2.2 Fate of Schwann Cells 394
28.2.3 Revascularization 395
28.2.4 Long Nerve Regeneration 396
28.3 The Nerve Allograft Response 397
28.4 Methods of Nerve Allograft Tolerance 398
28.4.1 Decrease Graft Antigenicity 398
28.4.2 Decrease Host Immune Response 401
28.5 Clinical Nerve Allotransplantation 404
28.6 Peripheral Nerve Allotransplantation in CTA 407
References 408
Live-Donor Nerve Transplantation 415
29.1 Introduction 415
29.2 OBPP 415
29.3 Cross-Chest C7 Nerve Transfer (Adapted fromGruber et al.1) 417
29.4 Nerve Transplantation in Animal Models 417
29.5 Peripheral Nerve Allografting: Clinical Experience 419
29.5.1 Case 1 419
29.5.2 Case 2 420
29.6 Clinical Hand Transplantation 421
29.7 Risks of Immunosuppression 421
29.8 Case Presentation (Adapted from Gruber et al.1) 422
29.8.1 Donor Evaluation and Procedure 424
29.8.2 Recipient Preparation 424
29.8.3 Recipient Procedure 425
29.8.4 Postoperative Care and Immunosuppressive Regimen 425
29.9 Results 427
29.9.1 Graft Rejection and Immunosuppression 427
29.9.2 Functional Recovery: Sensory Responses 427
29.9.3 Functional Recovery: Motor Responses 427
29.9.4 Functional Recovery: Needle Examination 428
29.9.5 Functional Recovery: Clinical Progress 429
29.10 Discussion (Adapted from Gruber et al.1) 430
29.11 Conclusion 430
References 431
Section VII 435
Ethical and Policy Concerns of Hand/Face Transplantation 436
30.1 Introduction 436
30.2 Innovative Surgery and Professional Responsibility 436
30.2.1 Risk-Benefit Assessment 436
30.2.2 Developing Standards and Oversight 437
30.2.3 The Consent Process 438
30.2.4 Patient Selection 440
30.3 Recipient-Related Concerns 441
30.4 Donor-Related Concerns 442
30.4.1 Dignified Treatment of the Deceased 442
30.4.2 Donor’s Family and Loved Ones 443
30.4.3 Donor Intent and Incentive 444
30.5 Conclusion 446
References 447
Ethical Debate on Human Face Transplantation 450
31.1 Introduction 450
31.2 Surgical Challenge 451
31.3 Immunosuppression and Rejection 453
31.4 Ethical Debate 455
31.4.1 On the Recipient 456
31.4.2 On the Donor 456
31.4.3 On the Population 456
31.5 Conclusion 457
References 457
Psychosocial Issues in Composite Tissue Allotransplantation 459
32.1 Introduction 459
32.2 CTA and Risk Acceptance 460
32.3 The Face in Social Interaction and the Psychosocial 461
32.3.1 Consequences of Disfigurement 461
32.4 Discussion 463
32.5 Conclusion 464
References 465
Composite Tissue Transplantation in the Twenty- First Century 467
33.1 Introduction 467
33.2 In the Future 467
33.2.1 April 15, 2045 Orange County Regional Composite Tissue Transplant Center
33.3 A Short Course of History 468
33.4 Looking Forward 470
33.5 What About Regeneration? 471
33.6 Back to the Future 472
33.6.1 August 15, 2100 Keynote Address to the Society of Interplanetary Surgeons
Index 474
Color Plates 485