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Ethical aspects in xenotransplantation
Ethical Aspects in Xenotransplantation R. Cortesini
S
OLID organ transplantation has been occasionally as well as unsuccessfully performed since 1906.1 Progressive improvements in surgical techniques and immunosuppressive therapy were made possible in the 1960s and prolonged survival was achieved after kidney transplantation from a chimpanzee to a human in both the USA and in Europe.2 The increasing availability of dialysis therapy and kidney transplantation from cadaver or living related and unrelated kidney donors reduced the interest in xenotransplantation, but it has again recently become an attractive option, at least for temporary replacement of heart and liver. Animal cells are also increasingly being used to treat metabolic and degenerative diseases (such as Parkinson’s disease) in human patients.3 However, chimpanzees and baboons are costly to obtain, have smaller organs, and can cause zoonoses.5 A better choice for xenotransplantation may be offered by pigs, which have anatomic and metabolic characteristics similar to humans.6 A “discordant” xenotransplantation, such as from swine to human, is associated with humoral hyperacute rejection, due to preformed antibodies, together with complement system activation (both classical and alternative ways) and cellular necrosis.7 Complement activation inhibitors may be soluble (H or C4bp) or membrane-bound: CR1 (CD35), decay accelerating factor (DAF o CD55),8 membrane cofactor protein (MCP o CD46), and CD59. The organs harvested from pigs transgenic for DAF, MCP, and CD59, would be protected by complement attack when grafted into human recipients.9 –11 Xenotransplantation of cells and organs raises three main ethical issues. The first involves the potential recipient who will undergo a procedure that is still experimental, although validated by much animal research work and some previous clinical experience. A pool recently taken in Great Britain among aged, high-risk patients enlisted for heart transplantation demonstrated a theoretical wide acceptance of organs from pigs, as opposed to a long and possibly unsuccessful wait for a human organ. Potential recipients of a transgenic pig liver xenoperfusion or xenotransplantation could be in hepatic encephalopathy and, therefore, informed consent could be provided only by relatives, who would face a very difficult choice. Another ethical problem not yet satisfactorily investigated is the possible psychological stress of receiving an
animal organ, even for a short period of time and as a temporary measure until a human donor is available. Furthermore, some people, not only animal rights activists, consider the production of transgenic animals (and vegetables) an intolerable violation of natural laws. However, Christian and also Hebraic and Islamic religious leaders12 do not have objections to xenotransplantation from transgenic pigs. A final, relevant ethical issue is the problem of xenozoonoses: the potential benefit of a few very sick patients could jeopardize the health of the entire population by mutational and recombinant events regarding animal retroviruses (a virus that inserts its genetic material directly into host DNA) in the human recipient. Presently, the risk of zoonoses is probably too high in the case of primate donors13 but not in the swine. Transgenic pigs may be more hazardous, as DAF is a receptor for several picornaviruses and CD46 for morbilliviruses; that is, animal versions of these viruses may become adapted for human infection. Recently, there has been evidence in PK-15 pig cell lines14 of humantropic C-type retroviruses15 that can infect human cells in vitro; however, it is still unknown if this will also happen in vivo and if it will cause degenerative diseases, immunodeficiency, or cancer. C-type retroviruses have a short half-life and infect only dividing cells expressing the appropriate receptor for the specific virion envelope protein; transmission takes place by transplacental and tissue exchange or sexual intercourse. However, infected human cells generally lack a(1–3)a residues and would therefore be resistant to human complement-mediated lysis, while immunosuppression would make recipients more prone to infection. The Center for Disease Control and Prevention is currently developing specific molecular diagnostics for porcine endogenous retrovirus (PERV) and baboon endogenous retroviruses (BaEV), rapid multiple serotype assays for foamy viruses, and cell lines for retrovirus isolation.16 All xenogeneic cell, tissue, and organ recipients must
From the II Patologia Chirurgica, Universita` di Roma “La Sapienza,” Rome, Italy. Supported by the Consorzio Interuniversitario per Trapianti d’Organo. Address reprint requests to Dr Raffaello Cortesini, II, Patologia Chirurgica, Viale del Policlinico, 00161, Rome, Italy.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00687-3
Transplantation Proceedings, 30, 2463–2464 (1998)
2463
2464
undergo careful monitoring by PCR and serology to detect retroviral infection, and also should not have children and not donate blood or organs; furthermore, immunization against retroviruses should be considered. These public health issues have been discussed by a British Government report in January 1997 and by some draft guidelines on xenotransplantation issued by the U.S. Food and Drug Administration, which the National Institutes of Health are further elaborating. Although a moratorium has not yet been imposed, great caution17 must be taken by both researchers and by government agencies. The potential risk of retroviruses must be evaluated carefully while considering the benefits that cellular and organ transplantation could bring to patients.18
CORTESINI 5. Kalter SS: In Goldsmith EI, Mort-Jankowski J (eds): In Primates in Medicine (vol 8). Basel: Karger; 1973 6. Coates ME, Gustafsson BE (eds): The Germ-Free Animal in Biomedical Research. London: Laboratory Animals Ltd; 1984 7. Ross DN, In Shapiro H (ed): Experience With Human Heart Transplantation. Durban: Butterworths; 1969 8. Cary N, Moody J, Yannoutsos N, et al: Transplant Proc 25:400, 1993 9. White DJG, Oglesby T, Liszewski MK, et al: Transplant Proc 24:474, 1992 10. Pascher A, Poehlein C, et al: Transplant Int (suppl 1):S385, 1996 11. McCurry KR, Kooyman DL, et al: Nature Med 1:423, 1995 12. Sellami MM: Transplant Proc 25:2307, 1993 13. Cooper DKC: Transplant Proc (in press)
REFERENCES
14. Patience C, Takeuchi Y, Weiss RA: Nature Med 3:282, 1997
1. Jaboulay M: Lyon Med 107:575, 1906 2. Bailey L, Nehlsen-Cannarella SL, Concepcion W, et al: JAMA 254:3321, 1985 3. Isacson O, Breakefield X: Nature Med 3:964, 1997 4. Niekra´sz M, Ye Y, Rolf LL, et al: Transplant Proc 24:625, 1992
15. Le Tissier P, Stoye JP, et al: Nature 389:681, 1997 16. Chapman LE: Personal communication 17. Bach FH, Ferrane C, Soares M, et al: Nature Med 3:944, 1997 18. Anonymous: Nature Med 3:935, 1997
S
OLID organ transplantation has been occasionally as well as unsuccessfully performed since 1906.1 Progressive improvements in surgical techniques and immunosuppressive therapy were made possible in the 1960s and prolonged survival was achieved after kidney transplantation from a chimpanzee to a human in both the USA and in Europe.2 The increasing availability of dialysis therapy and kidney transplantation from cadaver or living related and unrelated kidney donors reduced the interest in xenotransplantation, but it has again recently become an attractive option, at least for temporary replacement of heart and liver. Animal cells are also increasingly being used to treat metabolic and degenerative diseases (such as Parkinson’s disease) in human patients.3 However, chimpanzees and baboons are costly to obtain, have smaller organs, and can cause zoonoses.5 A better choice for xenotransplantation may be offered by pigs, which have anatomic and metabolic characteristics similar to humans.6 A “discordant” xenotransplantation, such as from swine to human, is associated with humoral hyperacute rejection, due to preformed antibodies, together with complement system activation (both classical and alternative ways) and cellular necrosis.7 Complement activation inhibitors may be soluble (H or C4bp) or membrane-bound: CR1 (CD35), decay accelerating factor (DAF o CD55),8 membrane cofactor protein (MCP o CD46), and CD59. The organs harvested from pigs transgenic for DAF, MCP, and CD59, would be protected by complement attack when grafted into human recipients.9 –11 Xenotransplantation of cells and organs raises three main ethical issues. The first involves the potential recipient who will undergo a procedure that is still experimental, although validated by much animal research work and some previous clinical experience. A pool recently taken in Great Britain among aged, high-risk patients enlisted for heart transplantation demonstrated a theoretical wide acceptance of organs from pigs, as opposed to a long and possibly unsuccessful wait for a human organ. Potential recipients of a transgenic pig liver xenoperfusion or xenotransplantation could be in hepatic encephalopathy and, therefore, informed consent could be provided only by relatives, who would face a very difficult choice. Another ethical problem not yet satisfactorily investigated is the possible psychological stress of receiving an
animal organ, even for a short period of time and as a temporary measure until a human donor is available. Furthermore, some people, not only animal rights activists, consider the production of transgenic animals (and vegetables) an intolerable violation of natural laws. However, Christian and also Hebraic and Islamic religious leaders12 do not have objections to xenotransplantation from transgenic pigs. A final, relevant ethical issue is the problem of xenozoonoses: the potential benefit of a few very sick patients could jeopardize the health of the entire population by mutational and recombinant events regarding animal retroviruses (a virus that inserts its genetic material directly into host DNA) in the human recipient. Presently, the risk of zoonoses is probably too high in the case of primate donors13 but not in the swine. Transgenic pigs may be more hazardous, as DAF is a receptor for several picornaviruses and CD46 for morbilliviruses; that is, animal versions of these viruses may become adapted for human infection. Recently, there has been evidence in PK-15 pig cell lines14 of humantropic C-type retroviruses15 that can infect human cells in vitro; however, it is still unknown if this will also happen in vivo and if it will cause degenerative diseases, immunodeficiency, or cancer. C-type retroviruses have a short half-life and infect only dividing cells expressing the appropriate receptor for the specific virion envelope protein; transmission takes place by transplacental and tissue exchange or sexual intercourse. However, infected human cells generally lack a(1–3)a residues and would therefore be resistant to human complement-mediated lysis, while immunosuppression would make recipients more prone to infection. The Center for Disease Control and Prevention is currently developing specific molecular diagnostics for porcine endogenous retrovirus (PERV) and baboon endogenous retroviruses (BaEV), rapid multiple serotype assays for foamy viruses, and cell lines for retrovirus isolation.16 All xenogeneic cell, tissue, and organ recipients must
From the II Patologia Chirurgica, Universita` di Roma “La Sapienza,” Rome, Italy. Supported by the Consorzio Interuniversitario per Trapianti d’Organo. Address reprint requests to Dr Raffaello Cortesini, II, Patologia Chirurgica, Viale del Policlinico, 00161, Rome, Italy.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00687-3
Transplantation Proceedings, 30, 2463–2464 (1998)
2463
2464
undergo careful monitoring by PCR and serology to detect retroviral infection, and also should not have children and not donate blood or organs; furthermore, immunization against retroviruses should be considered. These public health issues have been discussed by a British Government report in January 1997 and by some draft guidelines on xenotransplantation issued by the U.S. Food and Drug Administration, which the National Institutes of Health are further elaborating. Although a moratorium has not yet been imposed, great caution17 must be taken by both researchers and by government agencies. The potential risk of retroviruses must be evaluated carefully while considering the benefits that cellular and organ transplantation could bring to patients.18
CORTESINI 5. Kalter SS: In Goldsmith EI, Mort-Jankowski J (eds): In Primates in Medicine (vol 8). Basel: Karger; 1973 6. Coates ME, Gustafsson BE (eds): The Germ-Free Animal in Biomedical Research. London: Laboratory Animals Ltd; 1984 7. Ross DN, In Shapiro H (ed): Experience With Human Heart Transplantation. Durban: Butterworths; 1969 8. Cary N, Moody J, Yannoutsos N, et al: Transplant Proc 25:400, 1993 9. White DJG, Oglesby T, Liszewski MK, et al: Transplant Proc 24:474, 1992 10. Pascher A, Poehlein C, et al: Transplant Int (suppl 1):S385, 1996 11. McCurry KR, Kooyman DL, et al: Nature Med 1:423, 1995 12. Sellami MM: Transplant Proc 25:2307, 1993 13. Cooper DKC: Transplant Proc (in press)
REFERENCES
14. Patience C, Takeuchi Y, Weiss RA: Nature Med 3:282, 1997
1. Jaboulay M: Lyon Med 107:575, 1906 2. Bailey L, Nehlsen-Cannarella SL, Concepcion W, et al: JAMA 254:3321, 1985 3. Isacson O, Breakefield X: Nature Med 3:964, 1997 4. Niekra´sz M, Ye Y, Rolf LL, et al: Transplant Proc 24:625, 1992
15. Le Tissier P, Stoye JP, et al: Nature 389:681, 1997 16. Chapman LE: Personal communication 17. Bach FH, Ferrane C, Soares M, et al: Nature Med 3:944, 1997 18. Anonymous: Nature Med 3:935, 1997