Klienditugi: 7440010 (E-R 10-18)

E-raamat: Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas: Volume 1

Edited by Robert J. Stratta, Edited by Giuseppe Orlando (Section of Transplantation, Wake Forest University Baptist Medical Center Medical Center Boulevard Winston-Salem, NC, USA), Edited by Rainer W.G. Gruessner, Edited by Lorenzo Piemonti (IRCCS Ospedale San Raffaele, Director of Diabetes Research Institute and Director of Human Islet Transplantati), Edited by Camillo Ricordi

Formaat: PDF+DRM
Ilmumisaeg: 09-Nov-2019
Kirjastus: Academic Press Inc
Keel: eng
ISBN-13: 9780128148341

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Formaat: PDF+DRM
Ilmumisaeg: 09-Nov-2019
Kirjastus: Academic Press Inc
Keel: eng
ISBN-13: 9780128148341

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Transplantation, Bioengineering, and Regeneration of the Endocrine Pancreas, Volume 1, sets a new standard in transplant and regenerative medicine. The book details the-state-of-the-art in modern whole pancreas and islet transplantation, including donor selection, immunosuppression, complications, allograft pathology, and more. As regenerative medicine is changing the premise of solid organ transplantation, this volume catalogs the technologies being developed and the methods being implemented to bioengineer or regenerate the endocrine pancreas in order to more effectively treat diabetes. Edited and authored by unparalleled leaders in the field, this new volume argues for a much needed synergy between organ transplantation and regenerative medicine.

Provides comprehensive and cutting-edge knowledge of whole pancreas and islet transplantation
Includes sections that address donor selection, immunosuppression, complications, allograft pathology, and more
Offers an update on the progress of regenerative medicine research aimed at beta cells replacement in the treatment of diabetes

Contributors

xvii

Preface

xxiii

A Whole pancreas allo-transplantation

Section I Introduction

1 History of pancreas transplantation

David E.R. Sutherland

Rainer W.G. Gruessner

The first attempt at transplantation of pancreatic tissue

(1)

The nature of the pancreas

(1)

Discoveries about the pancreas

(1)

Discoveries about the relationship between pancreas and diabetes

(2)

Discoveries about insulin and diabetes etiology

(1)

Early animal models of diabetes and pancreas transplantation

(1)

Modern animal models of pancreas transplantation and surgical techniques

(2)

Modem animal models of pancreas transplant immunology

(1)

History of pancreas transplantation in humans

(9)

Acknowledgments

(1)

References

(9)

2 How to build a pancreas transplant program

Peter Abrams

Asha Zimmerman

John A. Powelson

Jonathan A. Fridell

Introduction

(1)

Leadership commitment to growth in pancreas transplantation

(1)

Growing the pancreas transplant waitlist through reevaluation of diabetic kidney waitlist patients

(1)

Growing the pancreas transplant waitlist through expanded recipient eligibility criteria

(1)

Modification of kidney transplant evaluation of new patients

(1)

Promotion of pancreas transplant for diabetic kidney transplant recipients (PAK)

(1)

Promotion of solitary pancreas transplants for hypoglycemic unawareness

(1)

Modification of clinical outreach to promote pancreas transplantation

(1)

Modification of donor call to promote pancreas transplant

(1)

Modification of donor pancreas acceptance rates

(1)

Simplifying pancreas transplant management through use of protocols

(1)

Conclusions

(1)

References

(2)

3 Pathophysiology of diabetes

Manfredi Tesauro

Francesco Antonio Mazzotta

Introduction

(1)

Insulin structure, secretion, and action

(4)

Type 1 diabetes

(1)

Type 2 diabetes

(3)

References

(3)

4 Epidemiology of diabetes mellitus

Kavya Chitra Mekala

Alain Gerald Bertoni

History/classic definitions

(2)

Special populations

(1)

Descriptive epidemiology

(1)

Risk factors

(1)

Diabetes complications

(2)

Treatment

(1)

References

(5)

Section II The donor

5 Pancreas donor selection

David A. Axelrod

Dixon B. Kaufman

Introduction

(1)

The ideal pancreas donor

(5)

Logistical aspects to optimize organ viability

(1)

Conclusion

(1)

References

(2)

6 Deceased donor pancreas procurement

Anand S. Rathnasamy Muthusamy

Jeevan Prakash Gopal

Vassilios E. Papalois

Donor selection

(1)

Assessment of the potential pancreas donor

(1)

Evolution of practice

(1)

Preoperative preparation

(1)

Surgical technique

(3)

Pancreas preservation

(1)

En bloc technique for pancreas-liver procurement

(1)

DCD procurement

(2)

Arterial variations in combined pancreas and liver procurement

(1)

Procurement with small bowel

(1)

Procurement without liver

(1)

Summary

(1)

References

(3)

7 Surgical techniques for living donor pancreas transplantation

Sidharth Sharma

Kaylene Barrera

Rainer W.G. Gruessner

Introduction

(1)

Selection criteria for donors

(1)

Donor operation

(5)

Postoperative management

(1)

Donor complications

(1)

Recipient operation

(3)

Variations in operative technique

(2)

Conclusions

(1)

References

(2)

8 Pancreas preservation

John O'Callaghan

Rutger Ploeg

Introduction

(1)

Organ damage after death

(1)

Cold storage and its effects

(4)

References

102

(3)

9 Pancreas graft back-table surgery technique

Paulo N. Martins

Giuseppe Orlando

Adel Bozorgzadeh

Introduction

105

(1)

Classical technique with sutures/ties

105

(5)

Tieless technique with bipolar device

110

(1)

Methods (description of technique)

110

(1)

Conclusion

111

(1)

References

111

(1)

Further reading

112

(3)

Section III The recipient

10 Pancreas transplant alone

Clark D. Kensinger

Jon S. Odorico

Robert R. Redfield

Introduction

115

(1)

Indications

116

(1)

Pretransplant evaluation

117

(2)

Donor selection: Avenues to increase pancreas utilization

119

(1)

Preoperative transplant assessment

119

(1)

Recipient operation

119

(1)

Immunosuppression

120

(1)

Postoperative management

120

(1)

Complications

121

(1)

Rejection

121

(1)

Outcomes

122

(1)

Summary

122

(1)

References

123

(2)

11 Pancreas after kidney transplantation

Joel T. Adler

Jon S. Odorico

Introduction

125

(1)

Indications and options for uremic diabetes

126

(2)

Operative concerns and immunologic challenges for PAK

128

(1)

Outcomes: Graft and patient survival

129

(1)

Future directions and challenges

130

(1)

References

130

(3)

12 Simultaneous pancreas-kidney transplantation

Irene Mosca

Edward Sharples

Sanjay Sinha

Peter J. Friend

Introduction

133

(1)

History

134

(1)

Epidemiology

134

(1)

Indications

134

(1)

Recipient selection

135

(1)

Donor characteristics

135

(1)

Outcomes

136

(2)

Immunosuppression

138

(1)

Maintenance

139

(1)

Antiproliferative agents

140

(1)

Surgical techniques

140

(1)

Implantation

141

(1)

Complications

142

(2)

Medical postoperative complications

144

(1)

Immunological complications

144

(1)

Infections

145

(1)

Surgical late complications

145

(1)

SPK and pregnancy

146

(1)

References

146

(2)

Further reading

148

(1)

13 Surgical techniques for deceased donor pancreas transplantation

Sidharth Sharma

Kaylene Barrera

Rainer W.G. Gruessner

Introduction

149

(1)

Management of exocrine pancreatic secretions: Bladder vs enteric drainage

149

(4)

Venous outflow: Systemic vs portal drainage

153

(1)

Graft size: Whole organ vs segmental transplants

154

(1)

Graft placement: Intraperitoneal vs extraperitoneal implantation

155

(1)

Surgical variations and technical modifications

156

(7)

Other types of pancreas transplants

163

(1)

Robotic techniques

164

(1)

Conclusion

164

(1)

References

164

(5)

14 Robotic pancreas transplantation

Sara Iacopi

Vittorio Grazio Perrone

Fabio Vistoli

Ugo Boggi

Introduction

169

(3)

Donor procedure

172

(2)

Other techniques for robotic PTx

174

(1)

Conclusions

175

(1)

References

176

(3)

15 Pancreas transplantation in the setting of multivisceral transplantation

Mahmoud Morsi

Gaetano Ciancio

Javier Gonzalez

Ahmed Farag

Rodrigo Vianna

Introduction

179

(1)

Indications and types of grafts

180

(2)

Contraindications

182

(1)

Donor selection

182

(1)

Donor surgery

183

(1)

Recipient surgery

183

(1)

Immunosuppression

184

(1)

Postoperative management

185

(1)

Monitoring of the pancreas graft

186

(1)

Outcomes and complications

186

(1)

Infections

187

(1)

Rejection

188

(2)

GVHD

190

(1)

Chronic kidney disease

190

(1)

References

190

(5)

16 Imaging in pancreas transplantation

Brenda Lee Holbert

Neeraj Lalwani

Preoperative planning: Imaging of potential recipient

195

(1)

Preoperative planning: Imaging of donor

195

(1)

Postoperative imaging

196

(1)

Sonography

196

(3)

Computed tomography and magnetic resonance imaging

199

(1)

Interventional imaging

200

(1)

Complications

200

(6)

Conclusion

206

(1)

References

206

(3)

17 Postoperative care of the pancreas transplant patient

X. Wittebole

P.F. Laterre

D. Castanares-Zapatero

M. Mourad

C. Collienne

Introduction

209

(1)

Perioperative care

210

(1)

General postoperative care

211

(2)

Nutrition

213

(1)

Somatostatin and analogues

213

(1)

Immunosuppression

214

(1)

Prevention of vascular graft vein thrombosis

214

(1)

Other specific surveillance

214

(1)

Conclusion

214

(1)

References

214

(3)

18 Immunosuppression for pancreas allo-transplantation

David I. Harriman

Jeffrey Rogers

Introduction

217

(1)

Induction therapy

218

(3)

Maintenance therapy

221

(2)

Antirejection treatment

223

(1)

Infections and immunosuppression

224

(1)

Immunosuppression and malignancy in PTX

225

(1)

Immunosuppressive therapy and pregnancy

225

(1)

Conclusion

225

(1)

References

226

(5)

Section IV Complications after pancreas allo-transplantation

19 Infectious complications after pancreas allotransplantation

Paolo Antonio Grossi

Introduction

231

(1)

Evaluation for infection before transplantation

231

(1)

Perioperative prophylaxis

232

(1)

Surgical site infections

232

(1)

Urinary tract infections

233

(1)

Bacteremia

233

(1)

Cytomegalovirus infection

233

(2)

BK virus infection

235

(1)

Donor-derived infections

235

(1)

Pancreas transplantation in HIV-infected individuals

235

(1)

Conclusions

236

(1)

References

236

(1)

Further reading

237

(3)

20 Medical complications after pancreas transplantation

Christoph Troppmann

Hyperglycemia

240

(1)

Hypoglycemia

241

(1)

Pancreatitis

242

(1)

Gastrointestinal bleeding

243

(1)

Loss of native kidney function (pancreas transplant alone recipients only)

243

(1)

Other medical complications specific to bladder-drained grafts

244

(1)

References

245

(2)

21 Technical complications of pancreas allotransplantation

David I. Harriman

Alan Farney

Introduction

247

(1)

Surgical techniques/considerations

247

(2)

Pretransplant complications

249

(1)

Intraoperative complications

249

(1)

Posttransplant complications

250

(6)

Conclusion

256

(1)

References

256

(3)

22 Pancreas transplantation, bioengineering, and regeneration

Jean-Paul G. Squifflet

Angelika C. Gruessner

Rainer W.G. Gruessner

Introduction: Clinical presentation of pancreas rejection through the evolution of surgical techniques and immunosuppressive therapies

259

(2)

Epidemiology and risk factors for pancreas rejection

261

(3)

Evaluation means of diagnosing rejection

264

(5)

Clinical presentation of pancreas graft dysfunction and rejection

269

(1)

Confirming the diagnosis of pancreas allograft rejection

270

(2)

Treatment of pancreas transplant rejection

272

(1)

Summary and recommendations

272

(1)

References

272

(7)

Section V Natural history

23 Reversal of secondary complications of type 1 diabetes (nephropathy, neuropathy, retinopathy, and cardiopathy)

Caterina Conte

Antonio Secchi

Introduction

279

(1)

Nephropathy

279

(3)

Neuropathy

282

(2)

Retinopathy

284

(2)

Cardiopathy

286

(2)

Summary

288

(1)

References

289

(6)

24 Recurrence of type 1 diabetes following simultaneous pancreas-kidney transplantation

George W. Burke

Gaetano Ciancio

Mahmoud Morsi

Jose Figueiro

Linda Chen

Francesco Vendrame

Alberto Pugliese

Preamble

295

(2)

Introduction

297

(11)

Future considerations

308

(1)

Network for the pancreas organ donors with diabetes

309

(1)

Conclusions

309

(1)

Acknowledgment

309

(1)

References

310

(3)

25 Pathological evaluation of whole pancreas transplants

Cinthia B. Drachenberg

John C. Papadimitriou

Joseph R. Scalea

Introduction

313

(2)

Acute rejection in the duodenal cuff

315

(1)

Histological diagnosis and grading of acute allograft rej ection---Banff schema

315

(6)

Other (nonrejection) histological diagnoses

321

(3)

Correlation between pathological findings and time and type of WPnTx dysfunction

324

(1)

References

324

(5)

26 Failure of the pancreas allograft

Diego Cantarovich

Delphine Kervella

Julien Branchereau

Georges Karam

Definition of pancreas allograft failure

329

(1)

Epidemiology of pancreas allograft failure

330

(1)

Causes of pancreas allograft failure

331

(1)

Risk factors of pancreas allograft failure

332

(2)

Evaluation of glucose homeostasis to predict long-term allograft failure

334

(2)

Therapeutic issues

336

(1)

Conclusions and prospects

336

(1)

References

337

(2)

27 Pancreas retransplantation

Ty B. Dunn

Karthik V. Ramanathan

Introduction

339

(1)

Historical perspective

339

(1)

Indications and considerations

340

(1)

Retransplant type and outcomes

341

(1)

Recipient evaluation

342

(2)

Donor selection

344

(1)

Timing

344

(1)

Surgical approaches

344

(1)

Postoperative care

345

(1)

Summary

345

(1)

References

345

(4)

Section VI State of the art of pancreas transplantation

28 The current state of pancreas transplantation in the United States---A registry report

Angelika C. Gruessner

Rainer W.G. Gruessner

Introduction

349

(1)

Statistical methods

350

(7)

Discussion

357

(1)

References

358

(1)

29 Trends in pancreas transplantation in the United States

Jesse D. Schold

Introduction

359

(1)

Number of pancreas transplant recipients

359

(1)

Demographic characteristics of pancreas transplant recipients and donors over time

360

(1)

Transplant volume by center

361

(1)

Outcomes following transplantation

361

(1)

Summary

361

(3)

References

364

(1)

30 Experimental pancreas transplantation

Erin Chang

John Renz

Rainer W.G. Gruessner

Introduction

365

(1)

Small animal models

365

(3)

Summary

368

(1)

Large animal models

368

(3)

Summary

371

(1)

References

371

(4)

31 Pancreas transplantation: Current issues, unmet needs, and future perspectives

Robert J. Stratta

Angelika C. Gruessner

Rainer W.G. Gruessner

Introduction

375

(2)

Improving outcomes in the setting of fewer transplants being performed

377

(4)

Donor, recovery, and preservation issues

381

(1)

Pancreas allocation and donor risk indices

381

(1)

Surgical techniques

382

(1)

Recipient selection and waiting list considerations

382

(1)

Immunosuppression and immunological outcomes

383

(1)

Pancreas vs islet transplantation

383

(1)

Summary and conclusions

384

(1)

References

384

(7)

B Islet allo-transplantation

Section I Introduction and indications

32 Treatment of type 1 diabetes complicated by problematic hypoglycemia

Peter Jacob

Suresh Rama Chandran

Pratik Choudhary

Introduction

391

(1)

How common is problematic hypoglycemia in type 1 diabetes?

392

(1)

Risk factors for problematic hypoglycemia

393

(1)

Approach to a patient with problematic hypoglycemia

394

(3)

Hypoglycemia and the role of different insulins

397

(1)

Use of technology

398

(5)

Summary

403

(1)

References

403

(4)

33 Eligibility of patients with type 1 diabetes for islet transplantation alone

Thierry Berney

Mohamed Alibashe-Ahmed

Giacomo Gastaldi

Axel Andres

Introduction: Current status of islet transplantation alone

407

(1)

Indications for beta-cell replacement in the absence of renal insufficiency

408

(1)

Assessment of "problematic hypoglycemia" as an indication for ITA

408

(1)

Management of problematic hypoglycemia

409

(1)

Clinical efficacy of ITA in problematic hypoglycemia

410

(1)

Eligibility criteria for ITA

410

(2)

Inclusion and exclusion criteria in recent multicenter clinical trials

412

(1)

Selection for PTA vs ITA

412

(2)

A word on IAK transplantation

414

(1)

Perspectives

414

(1)

References

415

(2)

34 Islet vs pancreas transplantation in nonuremic patients with type 1 diabetes

Arya Zarinsefat

Peter G. Stock

Introduction

417

(1)

P-Cell replacement

417

(1)

Solid organ pancreas transplant

418

(1)

Islet transplantation

419

(2)

Recommendations for pancreas vs islet transplantation

421

(2)

References

423

(2)

35 Simultaneous islet-kidney and islet-after-kidney transplantation

Roger Lehmann

Introduction

425

(1)

Treatment strategy in patients with end-stage kidney disease with and without a history of severe hypoglycemia

426

(1)

Treatment algorithm for beta-cell replacement therapy depends on kidney function

427

(2)

Indications and exclusion criteria for islet or pancreas transplantation (for SIK/SPK, IAK/PAK, or ITA/PTA)

429

(1)

Conclusions

429

(2)

References

431

(2)

36 Pancreatic islet transplantation in cystic fibrosis: Lung and islet transplantation

Laurence Kessler

Michel Greget

Dominique Grenet

Anne Olland

Thierry Berney

Romain Kessler

Introduction

433

(1)

Techniques

434

(1)

Immunosuppression

435

(1)

Indications

435

(1)

Results

435

(2)

Complications

437

(1)

Perspectives

437

(1)

Acknowledgments

437

(1)

References

437

(2)

37 Combined liver and islet transplantation in hepatogenous diabetes, cluster exenteration, and cirrhosis with type 1 diabetes

Marco Infante

Nathalia Padilla

Srigita Madiraju

Ana Alvarez

David Baidal

Camillo Ricordi

Rodolfo Alejandro

Introduction

439

(1)

Epidemiology, diagnosis, and prognosis of HD

440

(1)

Pathophysiology of HD

440

(2)

Treatment of HD

442

(1)

Liver transplantation

443

(1)

Combined liver and islet transplantation after upper abdominal exenteration

444

(1)

Combined liver and islet transplantation in patients with HD/T2DM

445

(2)

Combined liver and islet transplantation in patients with cirrhosis and T***1DM

447

(3)

Combined liver and pancreas transplantation in cirrhotic patients with T***1DM or HD/T2DM

450

(1)

Concluding remarks

450

(1)

References

451

(6)

Section II Donor selection

38 Evolving approaches to organ allocation for the whole pancreas vs islet transplantation

Oscar K. Serrano

Raja Kandaswamy

Introduction

457

(1)

Indications and definition of success after p-replacement

458

(1)

Edmonton protocol

458

(1)

Donor risk stratification

458

(1)

Impact of donor age

459

(1)

Impact of donor obesity

459

(1)

Allocation scheme in the United Kingdom

460

(1)

Allocation scheme in the United States

460

(1)

Cost and reimbursement implications

460

(1)

Forging ahead toward insulin-independence

461

(1)

References

462

(3)

39 Living donors

Takayuki Anazawa

Mitsukazu Gotoh

Introduction

465

(1)

Background of living donor islet transplantation

465

(1)

First report of living donor islet transplantation

466

(1)

Can we expand living donor islet transplantation?

467

(1)

Conclusion

468

(1)

Conflicts of interest

469

(1)

References

469

(2)

40 Pancreatic islet isolation from donation after circulatory death pancreas

Jason B. Doppenberg

Marten A. Engelse

Eelcoj P. Dekoning

Introduction

471

(1)

History

471

(1)

Donation after brain death

472

(1)

Donation after circulatory death

472

(1)

Ischemic time intervals

472

(2)

Controlled DCD perfusion technique

474

(1)

Prevalence of DCD

474

(1)

Graft outcomes in DCD kidney and liver transplantation

475

(1)

DCD vascularized pancreas transplantation

475

(1)

Donor selection for pancreas retrieval in DCD donors

475

(1)

Clinical outcome of vascularized DCD pancreas transplantation

475

(1)

Donor selection for DCD pancreatic islet isolation

476

(1)

Pancreatic islet isolation from DCD pancreas

476

(1)

Islet in vitro function after islet isolation from DCD pancreas

476

(1)

Clinical outcome of islet transplantation using DCD pancreas

477

(1)

Future perspectives

477

(2)

Conclusion

479

(1)

References

479

(6)

Section III Islet isolation

41 Factors related to successful clinical islet isolation

Wayne J. Hawthorne

Introduction

485

(1)

Clean rooms, equipment, and essentials for islet isolation

486

(3)

Donor and pancreas impacts

489

(3)

Donor retrieval and perfusion of the pancreas

492

(1)

Donor factor effects

493

(2)

Processing effects

495

(1)

Receipt and pancreas preparation

495

(1)

Minimization of potential contaminants

496

(1)

Distension and digestion of the pancreas

496

(2)

Density separation

498

(2)

Postisolation culture and quality assurance

500

(1)

Discussion

501

(1)

Acknowledgments

501

(1)

References

501

(2)

42 Pancreas and islet preservation

Klearchos K. Papas

Hector De Leon

Introduction

503

(1)

Key determinants of islet yield, function and viability during preservation

504

(3)

Pancreas preservation prior to islet isolation

507

(6)

Islet preservation during isolation, culture, and distribution

513

(3)

Islet preservation during culture and distribution

516

(2)

Outlook

518

(1)

References

519

(10)

43 Collagenases in pancreatic islet isolation

Ibrahim Fathi

Masafumi Goto

Introduction

529

(1)

Basic structure

529

(5)

ECM of the pancreas with emphasis on the peri-insular region

534

(1)

Role of different enzyme fractions in pancreatic digestion

535

(2)

Pancreatic dissociation enzymes in clinical islet isolation: Evolution, safety, and overview of commercial products

537

(4)

Exogenous parameters affecting collagenase digestion

541

(1)

Tailored approach to islet isolation

542

(1)

Conclusions

542

(1)

References

543

(5)

44 Predicting the function of islets after transplantation

Carly M. Darden

Anne Elizabeth Farrow

Shanthini K. Rajan

Muhaib Lakhani

Michael C. Lawrence

Bashoo Naziruddin

Introduction

548

(1)

Glucose tolerance and stimulation tests

548

(1)

Indices for solitary transplantation

549

(2)

Biomarkers of graft failure

551

(2)

Proteins

553

(2)

Nucleic acids

555

(2)

Current noninvasive imaging techniques for pancreatic islet transplantation

557

(2)

Summary

559

(1)

References

559

(6)

Section IV Outcomes after allogeneic pancreatic islet transplantation

45 Metabolic and endocrine evaluation of islet transplant function

Michael R. Rickels

Introduction

565

(1)

Glycemic control

566

(1)

Glucose tolerance

567

(1)

β-Cell function

568

(1)

Cell secretory capacity

568

(2)

Cell stress

570

(1)

Insulin-dependent glucose disposal (insulin sensitivity)

571

(1)

Insulin-independent glucose disposal (glucose effectiveness)

572

(1)

α-Cell function and glucose counterregulation

573

(1)

Conclusion

574

(1)

Acknowledgments

574

(1)

References

574

(5)

46 Procedure-related and medical complications in and after intraportal islet transplantation

Frances Tangherlini Lee

Xunrong Luo

Introduction

579

(1)

General overview of complication incidence related to intraportal ICT

579

(1)

Differences in complication rates between allogeneic and autologous islet cell transplantation

580

(1)

Complications related to percutaneous islet cell transplantation

580

(5)

Medical complications of islet cell transplantation

585

(3)

Closing remarks

588

(1)

References

588

(3)

47 Secondary complications of diabetes

Fanny Buron

Olivier Thaunat

Introduction

591

(1)

Nephropathy

591

(2)

Retinopathy

593

(1)

Neuropathy

593

(1)

Cardiovascular disease

594

(1)

Conclusion

594

(1)

References

594

(6)

Section V Current clinical results

48 Treating diabetes with islet transplantation: Lessons learnt from the Nordic network for clinical islet transplantation

Bengt Von Zur-Muhlen

Hanne Scholz

Jarl Hellman

Olle Korsgren

Torbjorn Lundgren

Introduction

600

(1)

The development of networks

600

(1)

How can we better serve our patients by working in networks?

600

(1)

The islet isolation facilities within the NNCIT

601

(1)

Standard operational procedures

601

(1)

CoE for type 1 diabetes

602

(1)

Allocation of pancreas

602

(1)

Our current practice in islet transplantation in brief

603

(1)

Follow-up

604

(3)

A selection of NNCIT studies or reports

607

(3)

Conclusion

610

(1)

Acknowledgments

610

(1)

References

610

(4)

49 UK's nationally funded integrated islet transplant program

Anneliese Flatt

Claire Counter

Paul Johnson

James A.M. Shaw

Demonstration of successful steroid-free islet transplantation in the UK

614

(1)

Validation of islet transport protocol

614

(1)

National Institute for Health and Care Excellence assessment

614

(1)

National Health Service funding of an integrated program

614

(1)

Listing criteria/recipient assessment

615

(1)

Product release and transplantation

615

(1)

Posttransplant follow-up

616

(1)

Attainment of metabolic goals within the integrated UK program with locally isolated and transported islets

616

(1)

The UK Pancreas Allocation Scheme for whole organ and islet transplantation

616

(2)

Islet graft survival and metabolic outcomes within the integrated Pancreas Allocation Scheme

618

(1)

UKITC biomedical and psychosocial outcomes of islet transplant research

619

(2)

Next steps for the UKITC/NHS program

621

(1)

Concluding comments

622

(1)

References

622

(4)

50 Type 1 diabetes transplanted with allogenic islets within the Swiss-French GRAGIL network

Mohamed Ali Bashe-Ahmed

Sandrine Lablanche

Pierre-Yves Benhamou

Anne Wojtusciszyn

Pierre Cattan

Nadine Pernin

Laurence Kessler

Lionel Badet

Thierry Berney

Axel Andres

Introduction

626

(1)

Organisation of the GRAGIL network

626

(1)

Islet processing and transplantation

627

(1)

Evolution of islet transplantation protocols in the GRAGIL network and outcomes

628

(3)

Activity in the GRAGIL network

631

(2)

Islet transplantation in diabetic patients with cystic fibrosis within the GRAGIL network

633

(1)

Lessons learned from 20 years of the GRAGIL network---Conclusion

633

(1)

Acknowledgments

633

(1)

References

634

(3)

51 Optimizing primary graft function in islet allotransplantation: The Lille experience

Mikael Chetboun

Kristell Le Mapihan

Valery Gmyr

Violeta Raverdy

Thomas Hubert

Robert Caiazzo

Christian Noel

Julie Kerr-Conte

Marie-Christine Vantyghem

Francois Pattou

Introduction

637

(1)

Methods

638

(1)

Results

639

(4)

Discussion and perspectives

643

(1)

References

643

(2)

52 Treating diabetes with islet transplantation: Lessons from the Milan experience

Lorenzo Piemonti

Paola Maffi

Rita Nano

Federico Bertuzzi

Raffaella Melzi

Alessia Mercalli

Rossana Caldara

Barbara Antonioli

Paola Magistretti

Massimo Venturini

Francesco De Cobelli

Massimo Cardillo

Carlo Socci

Antonio Secchi

Introduction

645

(1)

Indication for beta-cell replacement in Italy

646

(1)

Pancreas transplantation activity in Italy

647

(1)

Pancreas transplantation cost

647

(1)

Islet transplantation in Italy

647

(3)

Islet transplantation cost

650

(1)

Major achievement of Milan experience

651

(3)

Main ongoing projects

654

(1)

Future plans

655

(1)

References

655

(4)

53 Treating diabetes with islet transplantation: Lessons from the University of Miami

Stephanie S. Camhi

David Baidal

Rodolfo Alejandro

Ana Alvarez

Nathalia Padilla

Elina Linetsky

Norma S. Kenyon

Camillo Ricordi

Introduction

659

(1)

Clinical islet transplantation experience at the University of Miami

660

(4)

Adjuvant therapies

664

(2)

Patient management

666

(1)

Psychosocial outcomes

667

(1)

Potential risks and complications

667

(1)

Conclusion

668

(1)

Acknowledgment

669

(1)

References

669

(2)

54 Treating diabetes with islet cell transplantation: Lessons from the Edmonton experience

Khaled Z. Dajani

A.M. James Shapiro

Introduction

671

(1)

The history of islet transplantation

672

(1)

The Edmonton protocol

673

(1)

Indication for islet transplantation

674

(1)

Islet isolation and transplantation

674

(4)

Immunosuppresion

678

(1)

Outcomes

679

(1)

Future directions

680

(1)

References

681

(6)

Section VI Monitoring of allogeneic islet grafts
55. Immune monitoring of allogeneic islets

Laura Dichiacchio

Joseph R. Scalea

Jonathan Bromberg

Introduction

687

(1)

Mechanism of rejection of pancreatic islet grafts

687

(1)

Nonimmune monitoring of pancreatic islet grafts

688

(2)

Immune monitoring of pancreatic islet grafts

690

(2)

Conclusion

692

(1)

References

692

(3)

56 Markers for beta-cell loss

Frans K. Gorus

Bart Keymeulen

Geert Martens

Introduction

695

(1)

Beta-cell loss after islet transplantation

696

(1)

Indirect markers of beta-cell loss

696

(2)

Direct markers of beta-cell loss

698

(8)

Conclusions and perspectives

706

(1)

References

706

(5)

57 In vivo quality control of human islets in the immunodeficient mouse to predict islet function in man: A retrospective study in 87 clinical transplants

Gianni Pasquetti

Julien Thevenet

Mikael Cheteoun

Alan Apete

Valery Gmyr

Nathalie Delalleau

Caroline Bonner

Marie-Christine Vantyghem

Thomas Hubert

Francois Pattou

Julie Kerr-Conte

Introduction

711

(2)

Methods

713

(1)

Results

714

(4)

Discussion

718

(4)

Conclusion

722

(1)

Perspectives

722

(1)

Acknowledgments

723

(1)

References

723

(1)

Further reading

724

(3)

Section VII Immunomodulatory technologies applied to islet transplantation

58 Progress toward islet transplantation tolerance

James F. Markmann

Charles G. Rickert

Introduction---Rationale for tolerance in islet transplantation

727

(1)

History of tolerance in solid organ transplantation

728

(1)

Tolerance strategies for islet transplantation

729

(5)

Advanced islet transplantation technologies and immune tolerance

734

(1)

Conclusion and future directions

735

(1)

References

735

(6)

59 Filling the gap to improve islet engraftment and survival using anti-inflammatory approaches

Erica Dugnani

Antonio Citro

Introduction

741

(1)

Inflammation prior islet isolation

742

(1)

Inflammation and isolation procedure

743

(1)

Peri-transplant inflammation

744

(2)

Posttransplant inflammation

746

(1)

Conclusion

747

(1)

References

747

(4)

60 Islet immunoisolation by macroencapsulation

Barbara Ludwig

Introduction

751

(1)

Key aspects in islet macroencapsulation

752

(3)

Recent and current clinical trials

755

(1)

Future perspectives

756

(1)

Conclusions

756

(1)

References

757

(4)

61 Islet immunoisolation by microencapsulation

Wf Kendall Jr

Ec Opara

Introduction

761

(2)

Brief pre-insulin history of diabetes

763

(1)

Brief review of medical treatment for diabetes

764

(2)

Brief history of pancreas research

766

(2)

Human islet transplants

768

(1)

Decline of pancreas transplants

769

(1)

Limitations with islet transplant

769

(1)

Gene therapy with attempts at modifying gene expression utilizing gene vectors or gene vaccines

770

(1)

Regenerative therapy of pancreatic p cells

770

(1)

Induction of graft tolerance by utilizing bone marrow transplantation or foreign antigen recognition blocking agents

771

(1)

Xenotransplantation

771

(1)

Genetic modification of porcine cells

772

(1)

Islet immunoisolation

773

(2)

Extravascular micro-devices

775

(2)

Other factors that affect pancreatic islet function and viability

777

(4)

Conformal coatings

781

(1)

Professional opinion

782

(1)

References

783

(4)

62 Recurrence of type 1 diabetes after beta-cell replacement

Paolo Monti

Introduction

787

(1)

The persistence of autoreactive memory T cells and B cells after the onset of T1D

788

(1)

The presence of autoreactive memory T cells and autoantibodies before islet transplant

789

(3)

Autoimmunity recurrence after islet or pancreas transplantation

792

(3)

References

795

(4)

Section VIII Cellular therapies in preclinical and clinical islet transplantation

63 T regulatory cell therapy in preclinical and clinical pancreatic islet transplantation

Georgia Fousteri

Maria Pia Cicalese

Introduction

799

(1)

Types of regulatory T cells and mechanisms of suppression

800

(2)

γδ T cells

802

(2)

Treg isolation and expansion protocols

804

(1)

Treg stability and how to improve it

805

(1)

Treg cell dose to meet the therapeutic target

805

(1)

Approaches to generate (allo)antigen-specific Tregs

806

(1)

Location of Treg infusion and function

807

(1)

Tregs alone or in combination with immunotherapy?

807

(1)

Timing of Treg infusion

808

(1)

Safety and survival in vivo

808

(2)

Ongoing Treg therapies in solid organ transplantation

810

(1)

Barriers and other logistics

811

(1)

Conclusions

812

(1)

References

812

(9)

64 Cellular therapies in preclinical and clinical islet transplantation: Mesenchymal stem cells

Olle Korsgren

Hanne Scholz

Introduction

821

(1)

Understanding the mechanisms of MSCs

822

(2)

MSCs and islets

824

(2)

Conclusion

826

(1)

References

826

(7)

65 Alternative transplantation sites for islet transplantation

Silvia Pellegrini

Introduction

833

(1)

The pancreas

834

(1)

The spleen

834

(2)

The kidney

836

(1)

The adrenal glands

836

(1)

Immunoprivileged sites

837

(1)

The bone marrow

838

(1)

The gastrointestinal tract

839

(1)

The urinary tract

840

(1)

The muscle

840

(1)

The subcutaneous space

840

(1)

The peritoneum

841

(1)

The omentum

841

(1)

Conclusions

842

(1)

References

842

(7)

Index

849

Giuseppe Orlando, MD, PhD, Marie Curie Fellow, is an Associate Professor and a kidney and pancreas transplant surgeon scientist at the Wake Forest University School of Medicine, in Winston Salem, USA. His research aims at developing platforms for the bioengineering and regeneration of transplantable organs, and at developing therapies to enhance the innate ability of the human body to repair itself after damage. His literature output aims at bridging organ transplantation to regenerative medicine. At the San Raffaele Scientific Institute (Milan, Italy) Lorenzo Piemonti serves as Director of Diabetes Research Institute and Director of Human Islet Transplantation Program. He also serves as Head of the Beta Cell Biology Unit (Diabetes Research Institute), Director of Human Islet Processing Facility, and coordinator of European Consortium for Islet Transplantation that has been providing Human beta Cell Products for research across state barriers in Europe since 2000. He also serves as Professor in Endocrinology at University Vita Salute San Raffaele” of Milan and as Honorary Visiting Professor at Vrije Universiteit of Brussel. His area of expertise is mainly focused on diabetes and pancreatology. In particular he has large experience about diabetes and pancreatic cancer. He had in the past studied the role of innate immunity in islet cell biology (especially in the human model of islet transplantation in type 1 diabetes recipient) and in pancreatic cancer biology (especially the role of chemokines and chemokine receptor system in inducing leukocytes infiltration). More recently, his research interests includes beta cell replacement, immune tolerance induction strategies, dendritic cell biology, stem cells. He currently serves as section Editor of Cell Transplantation-the Regenerative Medicine Journal and of Current Diabetes Reports, as editorial board of Acta Dibetologia, as Councilor of the International Pancreas and Islet Transplantation Association (IPITA) of The Transplantation Society (TTS), as member of the National Committee for Food Safety (2018-2021, Italian Ministry of Health) and previously (2011-2017) as member of the European Pancreas and Islet Transplantation Association (EPITA) committee of European Society for Organ Transplantation (ESOT). Lorenzo Piemonti authored more than 200 original articles published in peer-reviewed journals surveyed in PubMed. h-index (December 2018): 43 Web of Science; 47 Scopus; 53 Google Scholar. Considering the period 2001-2018 Lorenzo Piemonti authored a total of 165 original articles published in peer-reviewed journals for an impact factor of 918.344 (mean impact factor: 5.566) Camillo Ricordi holds the Stacy Joy Goodman Chair in Diabetes Research. He is Professor of Surgery, Distinguished Professor of Medicine, Professor of Biomedical Engineering, Microbiology and Immunology and Director of the Diabetes Research Institute (www.diabetesresearch.org ) and the Cell Transplant Program at the University of Miami. After developing the method for human pancreatic islet isolation, he led the team that performed the first series of successful clinical islet allotransplants to reverse diabetes. He is currently serving as Chairperson of the NIH funded Clinical Islet Transplantation (CIT) Consortium, which standardized cell manufacturing protocols in North America and Europe and just completed the first multicenter FDA Phase III trial of islet transplantation in the US. He is currently Editor-in-Chief of CellR4 (www.cellr4.org) and serves as Founding Chairman of The Cure Alliance (www.thecurealliance.org) and of the Diabetes Research Institute Federation (www.diabetesresearch.org).

In 2018 Ricordi was inducted into the National Academy of Inventors for contributing outstanding inventions that have made a tangible impact on quality of life, economic development, and welfare of society. That same year he was ranked as the #1 world expert in transplantation of insulin producing cells for treatment of diabetes, among over 4,000 physicians, surgeons and scientists evaluated. In 2019 Ricordi was appointed to the Supreme Council of Health (Consiglio Superiore di Sanita) by the Italian Ministry of Health.

Ricordi also serves as President of the Board of ISMETT (Mediterranean Institute of Transplantation and Advanced Therapies; http://www.ismett.edu), and was appointed President of Fondazione Ri.MED (http://www.fondazionerimed.eu) by the Italian Prime Minister, for the 2013-2017 term.

Ricordi was founding president of the Fondazione Cure Alliance ONLUS and of The Cure Alliance (www.thecurealliance.org) and Chairman of the Diabetes Research Institute Federation (http://www.diabetesresearch.org/Research-Collaboration), coordinating and promoting cure focused research at over 24 leading institutions worldwide, while further developing Telescience platform technologies to eliminate geographic barriers to scientific collaboration. These initiatives now allow scientists and project teams from around the world to synergize efforts and work together like if they are in the same physical space (https://www.corriere.it/cronache/19_febbraio_05/consiglio-superiore-sanita-n omine-7d42c47e-293e-11e9-950e-d545297d98ec.shtml).

Dr. Ricordi has been awarded 27 patents, has >1,000 scientific publications, >40,000 citations and a 95 H-index. Robert J. Stratta, MD, is Professor and Jesse H. Meredith Chair in Transplant Surgery and Director of Transplantation at Wake Forest Baptist Health, which is currently one of the largest kidney and pancreas transplant centers in the US. He also has a cross-appointment as a Professor both in Urology and with the Wake Forest Institute of Regenerative Medicine. He accepted this appointment in October 2001 following many years as Professor of Surgery and Director of Pancreas Transplantation at the University of Nebraska Medical Center and as Professor of Surgery at the University of Tennessee, Memphis. After earning his B.S. degree at the University of Notre Dame, Dr. Stratta received his M.D. degree from the University of Chicago-Pritzker School of Medicine and trained in General Surgery at the University of Utah. He then completed a transplant clinical and research fellowship at the University of Wisconsin-Madison. He is co-author of 6 books, 39 book chapters, 731 abstracts, 102 online commentaries, 423 oral presentations, and 439 peer-reviewed articles dealing predominantly with transplantation. He has accumulated more than $9 million in career research funding. He has been active in medical school, surgical resident, and transplant fellow education since 1988; is a member of 25 medical societies; three editorial and physician review boards each; and numerous local, regional, and national committees including United Network for Organ Sharing (UNOS) activities since 1988. His areas of research interest and expertise include kidney and pancreas allocation and transplantation, immunosuppressive strategies, organ donation and preservation, and expanded criteria donors. He is Past President of the Executive Board of Directors of Carolina Donor Services and was recently Councillor of UNOS Region 11 and a member of the UNOS Board of Directors. He has lectured worldwide on kidney and pancreas transplantation, has performed more than 2000 transplants in his career, is board certified in General Surgery, and has been selected as one of the Best Doctors in America since 1993, one of America's Top Surgeons since 2004, and is currently listed as one of Americas Top Doctors and the Patients Choice Award. Dr. Rainer W. G. Gruessner, MD, FACS, FICS, is Professor of Surgery at SUNY Downstate Health Sciences University. He formerly served as Chairmen of the Departments of Surgery at the University of Zurich, University of Arizona, and State University of New York. Dr. Gruessner is a nationally renowned surgeon and clinical innovator who has developed new surgical techniques for intestinal, pancreas, and liver transplants. He is prolific academic, a committed educator, and successful mentor to surgical and transplant faculty, residents and fellows. Dr. Gruessners academic accomplishments include more than 700 published manuscripts, review articles, book chapters, and published abstracts. Dr. Gruessner has been an invited speaker at over 170 institutions and meetings worldwide. Hes (co-) edited five textbooks: the standard textbooks on Transplantation of the Pancreas, Living Donor Transplantation, and Robotic Surgery and serving as senior editor of a textbook on Transplantation, Bioengineering and Regeneration of the Endocrine Pancreas and a textbook on Technological Advances in Surgery, Trauma and Critical Care. He has served as PI and co-investigator on over 20 research projects and clinical trials, supported by industry, foundations, and the NIH. Dr. Gruessner is a member of over 20 national and international professional societies, has organized many international congresses, is an editorial board member for about 10 journals and has served on many professional and societal committees. In 2019, he received the Richard C. Lillehei award from the International Pancreas and Islet Association (IPITA) for his lifetime achievements in the field of pancreas transplantation.

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