Strasbourg, 21 February 2003 [cdbi/cdbi-cdsp-xeno/doc/divers/ CDBI/CDSP-XENO (2003) 1 XENO(2003)1E state of art final] REPORT ON THE STATE OF THE ART IN THE FIELD OF XENOTRANSPLANTATION In 1999, the Committee of Ministers of the Council of Europe set up a Working Party on Xenotransplantation under the joint responsibility of the Steering Committee on Bioethics (CDBI) and the European Health Committee (CDSP) which decided to prepare a Report on the State of the Art in the field of Xenotransplantation. A previous version of this Report was used as a scientific basis for the preparation by the Working Party of a draft Recommendation on Xenotransplantation. TABLE OF CONTENTS 1. INTRODUCTION .............................................................................................................. 5 2. INTENTION OF DOCUMENT ........................................................................................... 7 3. OVERVIEW OF CONTENTS .............................................................................................. 9 4. DEFINITION ................................................................................................................... 16 5. RESEARCH IN THE FIELD OF XENOTRANSPLANTATION .............................................. 17 5.1. Recent activities in organ xenotransplantation ............................................................ 17 5.1.1. Heart xenotransplantation ............................................................................. 17 5.1.2. Liver xenotransplantation ............................................................................... 17 5.2. Recent activities in cellular xenotransplantation........................................................... 19 5.2.1. Transplantation of cells from the adrenal medulla.......................................... 20 5.2.2. Transplantation of cells producing neurotrophic growth factor ..................... 20 5.2.3. Transplantation of porcine neurons ............................................................... 20 5.2.4. Transplantation of pancreatic xenoislets ...................................................... 22 5.2.5. Transplantation of baboon bone marrow ....................................................... 23 5.2.6. Summary remarks relating to cellular xenotransplantation ........................... 23 5.3. Extracorporeal exposure to xenoorgans and xenocells ............................................... 23 5.3.1. Developments in the use of extracorporeal cellular xenotransplants ............ 23 5.3.2. Developments in the use of extracorporeal organ xenotransplants ............... 24 5.3.3. Conclusion ..................................................................................................... 25 5.4. Immunological and physiological challenges relating to xenotransplantation ............. 26 5.4.1. The Immunobiology of Xenotransplantation .................................................. 26 5.4.1.1. Hyperacute rejection ........................................................................... 27 5.4.1.2. Acute vascular rejection ..................................................................... 27 5.4.1.3. Acute cellular rejection ....................................................................... 28 5.4.1.4. Chronic rejection ................................................................................ 28 5.4.1.5. Strategies to prevent immunological rejection reactions ................... 28 2 5.4.2. The Physiology of organ xenotransplantation ............................................... 29 5.4.2.1. Heart xenotransplantation .................................................................. 29 5.4.2.2. Kidney xenotransplantation ................................................................ 29 5.4.2.3. Liver xenotransplantation ................................................................... 30 5.4.2.4. Conclusion ......................................................................................... 30 6. PRECLINICAL ACTIVITIES ............................................................................................. 31 6.1. The use of Non-human Primates in Xenotransplantation ............................................. 32 6.1.1. Microorganisms of non-human primates (with exception of retroviruses) and their transmission to humans .......................................................................... 33 6.1.2. Exogenous and endogenous retroviruses of non-human primates and their transmission to humans ........................................................................... 39 6.1.3. Non-human primates: General considerations on microbiological safety ..... 45 6.1.4. Health control considerations when using non-human primates ................... 46 6.1.5. Future prospectives in the use of non-human primates ................................. 47 6.1.6. Conclusion ..................................................................................................... 48 6.2. The use of Pigs in Xenotransplantation ........................................................................ 48 6.2.1. Risk of xenozoonosis when using pigs .......................................................... 48 6.2.2. Risk management for xenotransplant source animals ................................... 50 6.2.3. Conclusion ..................................................................................................... 52 7. CULTURAL, ETHICAL AND RELIGIOUS ASPECTS OF XENOTRANSPLANTATION ......... 53 7.1. Culture .......................................................................................................................... 53 7.2. Attitudes ....................................................................................................................... 55 7.3. National Policies ........................................................................................................... 60 7.4. International Organisations and Policies ..................................................................... 65 7.5. An Ethical Overview of Clinical Xenotransplantation ................................................... 66 7.5.1. “Interfering with nature” ................................................................................ 66 7.5.2. Issues of consent ........................................................................................... 67 7.5.3. The effects on others ..................................................................................... 67 7.5.4. Risk ................................................................................................................ 68 3 7.5.5. Commercial interests ..................................................................................... 68 7.5.6. The Public ...................................................................................................... 68 7.6. The Ethical and Welfare Issues relating to the Use of Animals for Xenotransplantation ............................................................................................................................................. 68 7.6.1. Questions regarding the ethical acceptability of using animals ..................... 69 7.6.2. Welfare issues for source animals ................................................................. 70 7.6.2.1.Techniques in Transgenesis .................................................................. 71 7.6.2.2. Derivation of ‘S/QPF’ animals ............................................................... 71 7.6.2.3. Husbandry and care .............................................................................. 71 7.6.2.4. Procedures and collection of organs .................................................... 72 7.6.2.5. Welfare issues for animals in research ................................................. 72 7.6.3. Licensing and control .................................................................................... 73 7.6.4. Conclusion ..................................................................................................... 74 7.7. Religious faiths and xenotransplantation ..................................................................... 74 8. LEGISLATIVE AND REGULATORY FRAMEWORKS ......................................................... 76 8.1. Surveys ........................................................................................................................ 76 8.2. Conclusion ................................................................................................................... 85 Glossary: ............................................................................................................................ 87 References: ......................................................................................................................... 90 4 1. INTRODUCTION Xenotransplantation (the transplantation of cells, tissues and organs from one species to another) was first considered almost a hundred years ago. Since then, there have been sporadic instances of clinical applications in the history of medicine but interest was only rekindled in the early 1990s as a result of new progress in the biomedical sciences. Indeed, because of the great success of allotransplantation (human to human) an ever increasing number of operations are being performed and the need for human transplants now exceeds many times the supply. It is because of this shortage and the possibility for scientists to create a virtually unlimited supply of transplants through the use of animal