Pro & Contra Organspende

Pro & Contra Organspende 27.11.2012, Bremen Bruno Reichart Ludwig Maximilians Universität München

Pro & Contra Organspende Anmerkungen: zur Wartezeit auf ein Organ, Gewebe zur Todesfeststellung mittels neurologischer Kriterien zum Deutschen Xenotransplantations Consortium

Clinical orthotopic heart transplantation, LMU

Pro & Contra Organspende Eurotransplant 2012

Pro & Contra Organspende Nierentransplantation Graft survival (%) Meier-Kriesche et al., Transplantation 2002;74:1377 81

Pro & Contra Organspende Cleveland et al., J Heart and Lung Transplant 2011 Aug;30(8):862-9 :

Pro & Contra Organspende Diabetes mellitus Epidemie Gesamtzahl der Diabetesfälle verdoppelt sich in den nächsten 20 Jahren; 10% der Patienten werden dem Typ1 zugeordnet Adapted from International Diabetes Federation

Pro & Contra Organspende Results after single islet transplantation, Dresden Centre 2008-2012 BG profile prior to Tx BG profile 3 yrs post Tx Patient demographics (n = 10) Age (yrs) Mean ± SD 47,3 ± 10,4 Male : female 2 : 6 Diabetes duration (yrs) 32,5 ± 12,9 HbA1c (%) 7,9 ± 0,9 BMI (kg/m²) 25,7 ± 2,6 Insulin requirement (IU/d) 40 ± 15,6 events/week 1.75 1.50 1.25 1.00 0.75 0.50 0.25 0.00 Hypoglycaemia (BG < 2,8 mmol/l) pre-tx 6 12 18 24 30 36 6-months periods after Tx Insulin requirement (IU/d) 70 60 50 40 30 20 10 0 Pre-Tx Insulin Requirement Today

Pro & Contra Organspende Anmerkungen: zur Wartezeit auf ein Organ zur Todesfeststellung mittels neurologischer Kriterien zum Deutschen Xenotransplantations Consortium

2012

Ein irreversibler Hirnausfall beendet seine gesamte senso-motorischen Integration Nach genauer Diagnosestellung ist eine Reversibilität der Befunde nie dokumentiert worden Der gesicherte irreversible Ausfall der Hirnaktivität gilt in Deutschland als ein sicheres Todeszeichen die Todesfeststellung mit neurologischen Kriterien ist wissenschaftlich gesichert

Papst Johannes Paul II. hat in einer Ansprache 2000 die moralische Gewissheit der Todesfeststellung durch das neurologische Kriterium bestätigt und ausgeführt: der Tod eines Menschen [ist] ein einzigartiges Ereignis, das in der vollkommenen Auflösung dieser Einheit und dieses integrierten Ganzen besteht, die das personale Selbst ausmacht. Er resultiert aus der Trennung des geistigen Lebensprinzips (oder Seele) von der leiblichen Person. Der in dieser ursprünglichen Bedeutung verstandene Tod der menschlichen Person ist ein Ereignis, das durch keine wissenschaftliche Technik oder empirische Methode unmittelbar identifiziert werden kann. Dennoch zeigt die menschliche Erfahrung, dass der Tod unweigerlich von bestimmten biologischen Kennzeichen begleitet ist In diesem Sinn sollte das in der heutigen Medizin angewandte Kriterium zur Feststellung des Todes nicht als die technisch-wissenschaftliche Bestimmung der genauen Todeszeit verstanden werden, sondern als eine wissenschaftlich zuverlässige Methode zur Identifizierung jener biologischen Anzeichen, die den Tod der menschlichen Person eindeutig beweisen. Rom, August 2000

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Dolling -Phänomen

Neurologische Hirntod-Diagnostik 2 N Engl J Med, Vol. 344, No. 16, April 2001

Transkraniele Doppler-Sonographie, Perfusions-Szintigramm N Engl J Med, Vol. 344, No. 16, April 2001

Neurologische Hirntod-Diagnostik: Fehlen des Atemantriebs N Engl J Med, Vol. 344, No. 16, April 2001

Pro & Contra Organspende Anmerkungen: zur Wartezeit auf ein Organ zur Todesfeststellung mittels neurologischer Kriterien zum Deutschen Xenotransplantations Consortium

The pig as a potential donor Domesticated species High fertility, great abundance, rapid growth Anatomy, physiology not too different from human Strict hygienic conditions possible Previous success with porcine insulin, heart valves, skin patches Genetic modifications possible

The pig as a potential donor Domesticated species High fertility, great abundance, rapid growth Anatomy, physiology not too different from human Strict hygienic conditions possible I like pigs. Dogs look up to us. Cats look down on us. Previous success with porcine insulin, heart valves, skin patches Genetic modifications possible

The pig as a potential donor I like pigs. Dogs look up to us. Cats look down on Domesticated species us. Pigs treat us as High fertility, great abundance, rapid growth equals. Anatomy, physiology not too different from human ( We agree Sir Winston) Strict hygienic conditions possible Previous success with porcine insulin, heart valves, skin patches Genetic modifications possible

Longest survival times of organ and cell xenotransplantations from (mostly tg) pigs to nonhuman primates The Lancet, Vol 379, Feb. 18, 2012

Start Hannover/Mariensee: SFB 265 and BMBF Gene Therapy Munich 1998-2004 : Support from multiple individual small grants, Bavarian Research Foundation (up to 1 m/year) 2003 Hannover/Mariensee and Munich start joint initiative 2004-2012 Hannover/Mariensee-Munich Transregio Research Group FOR 535 (up to 1.8 m/y) supported by the German Research Foundation 2004 Paul Ehrlich and Robert Koch Institutes join to address safety issues 2012-2016 Collaboration with the Technical University Dresden, Department of Medicine, integration within the CRC 127 (approx. 3.0 m/y); poss. extension till 2024

The new German Consortium A Immunity/Tolerance C Preclinical and clinical xenotransplantation A1 Genetic control of xenogeneic immune responses: studies in MHC- and NKC-congenic rat models (Schwinzer, Hundrieser) C1 Comparative biology of porcine and human islets in situ and after transplantation (Speier, Solimena, Bonifacio) A2 A3 Immunomodulation by viral vectors and endothelial adaptation (Hinkel, Kupatt) The islet / vascular inflammation interface in early xenograft dysfunction (Chavakis, Ludwig, Waskow) C2 Treatment of type 1 diabetes by transplantation with transgenic porcine islet expressing immunomodulatory molecules (Seissler) A4 Adoptive transfer of regulatory T-cells to modulate xenogeneic immune responses for transplantation (Pohla, Jaeckel) C3 Porcine islet macroencapsulation a concept for xenogeneic islet transplantation. Intrahepatic porcine islet xenotransplantation: integrated strategies for reduction of graft inflammation and immune rejection (Ludwig, Brendel, Bornstein) B B1 B2 B3 Novel transgenic strategies Improved transgenic pigs for pig-to-primate xenotransplantation (Niemann, Kues) Pigs deficient in the major xenoreactive non-gal antigen Neu5Gc (Schnieke, Flisikowska) Genetically engineered donor pigs with improved pancreatic islets (Klymiuk, Wünsch, Wolf) C4 C5 C6 Donor modification for reduction of ischemia/reperfusion (I/R) injury in kidney transplantation influence on allograft and xenograft function and coagulation (Winkler, Tiede, Johanning) Biomatrices - heart valves (Hilfiker, Haverich, Martin) Immunomodulatory and immunosuppressive strategies in preclinical experimental models of cardiac xenotransplantation (Brenner, Buchholz, Abicht) Z-Projects Z1: Ethical and legal issues, psycho-social implications, public relations, road map to clinical trials (Marckmann, Sautermeister, Reichart) Z2: Microbiological safety including virological safety (Denner, Tönjes) Z3: Core facility for large animals (Niemann, Schnieke, Wolf, Kaup)

The new German Consortium A Immunity/Tolerance C Preclinical and clinical xenotransplantation A1 Genetic control of xenogeneic immune responses: studies in MHC- and NKC-congenic rat models (Schwinzer, Hundrieser) C1 Comparative biology of porcine and human islets in situ and after transplantation (Speier, Solimena, Bonifacio) A2 A3 Immunomodulation by viral vectors and endothelial adaptation (Hinkel, Kupatt) The islet / vascular inflammation interface in early xenograft dysfunction (Chavakis, Ludwig, Waskow) C2 Treatment of type 1 diabetes by transplantation with transgenic porcine islet expressing immunomodulatory molecules (Seissler) A4 Adoptive transfer of regulatory T-cells to modulate xenogeneic immune responses for transplantation (Pohla, Jaeckel) C3 Porcine islet macroencapsulation a concept for xenogeneic islet transplantation. Intrahepatic porcine islet xenotransplantation: integrated strategies for reduction of graft inflammation and immune rejection (Ludwig, Brendel, Bornstein) B B1 B2 B3 Novel transgenic strategies Improved transgenic pigs for pig-to-primate xenotransplantation (Niemann, Kues) Pigs deficient in the major xenoreactive non-gal antigen Neu5Gc (Schnieke, Flisikowska) Genetically engineered donor pigs with improved pancreatic islets (Klymiuk, Wünsch, Wolf) C4 C5 C6 Donor modification for reduction of ischemia/reperfusion (I/R) injury in kidney transplantation influence on allograft and xenograft function and coagulation (Winkler, Tiede, Johanning) Biomatrices - heart valves (Hilfiker, Haverich, Martin) Immunomodulatory and immunosuppressive strategies in preclinical experimental models of cardiac xenotransplantation (Brenner, Buchholz, Abicht) Z-Projects Z1: Ethical and legal issues, psycho-social implications, public relations, road map to clinical trials (Marckmann, Sautermeister, Reichart) Z2: Microbiological safety including virological safety (Denner, Tönjes) Z3: Core facility for large animals (Niemann, Schnieke, Wolf, Kaup) Munich (LMU+TUM) Hannover Dresden

Our genetic toolbox Mono-transgenic pigs 1,3-Gal KO, CD46, CD55, CD59, thrombomodulin HO-1, A20, LEA 29Y, HLA-E/ 2m, TRAIL Multi-transgenic pigs 1,3-Gal KO + CD46 + thrombomodulin 1,3-Gal KO + CD46 + HO-1 1,3-Gal KO + CD46 + LEA 1,3-Gal KO + CD46 + TRAIL 1,3-Gal KO + CD46 + HLA-E CD46 + HLA-E Large transgene vectors CD46, CD55, CD59, and CD55/A20/HO-1 or CD55/TM/LEA Viral gene transfer in rats and pigs HO-1, thymosin 4, PD-L1

Valve replacement in children Hilfiker, C5 Percantage Mtd homograft Porcine Bovine Years UCT 1984

2009 2011: heterotopic thoracic xhtx (n=10) with double (GalT-KO/hCD46) and triple (GalT-KO/hCD46/hTM) genetically modified donors [Bauer et al., Xenotransplantation. 2010 May-Jun;17(3):243-9] [Barnard, Losman 1977]

Survival heterotopic thoracic xhtx 100 90 80 baboons, all (n=10) baboons, mishaps excluded (n=6) 70 60 % 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 postoperative day maximum survival of 50 days mean overall survival: 14 ± 4.6 days excluding 4 mishaps: 22 ± 5.7 days With conventional immunosuppression like in the allogeneic system a constant survival of more than 22 ± 5.7 days is not possible due to delayed humoral rejection

New co-operation Living Cell Technologies New Zealand (NZ), Diatranz Otsuka, Japan have established a designated pathogen-free (DPF) herd from Auckland Islands (in between NZ and the Antarctic) pigs a feral breed that has had essentially no contact with other pigs or humans for about 150 years and has subsequently been bred in isolation in New Zealand.

The new German Consortium Introducing xenogeneic tissues and organs into the clinic is an ambitious aim - but certainly possible within proposed 12 year period. Year 7/ 8 onwards Year 5 onwards Year 3-7 Year 1-7 Year 1-4 Year 1-4 Clinical trials GM porcine hearts / kidneys Clinical trials; GM porcine islets Preclinical experiments; GM porcine kidney transplants Preclinical experiments; GM porcine heart transplants Preclinical experiments; (encapsulated?) GM porcine islets Clinical trials; encapsulated WT porcine islets

Perspective Providing xenogeneic tissues and organ transplantations for the benefit of our patients

Pro & Contra Organspende Munich Hannover Dresden

Angiographie Spender Normalbefund

The Lancet, Vol 379, Feb. 18, 2012

Our genetic toolbox Mono-transgenic pigs 1,3-Gal KO, CD46, CD55, CD59, thrombomodulin HO-1, A20, LEA 29Y, HLA-E/ 2m, TRAIL Multi-transgenic pigs 1,3-Gal KO + CD46 + thrombomodulin 1,3-Gal KO + CD46 + HO-1 1,3-Gal KO + CD46 + LEA 1,3-Gal KO + CD46 + TRAIL 1,3-Gal KO + CD46 + HLA-E CD46 + HLA-E Large transgene vectors CD46, CD55, CD59, and CD55/A20/HO-1 or CD55/TM/LEA Viral gene transfer in rats and pigs HO-1, thymosin 4, PD-L1