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Outline of a Risk Assessment: The Welfare of Future Xeno-Donor Pigs

Published online by Cambridge University Press:  11 January 2023

K Dahl ,
P Sandøe ,
P F Johnsen ,
J Lassen  and
A Kornerup Hansen
K Dahl*
Affiliation:
Centre for Bioethics and Risk Assessment, The Royal Veterinary and Agricultural University, 15 Bülowsvej, DK-1870 Frederiksberg C, Denmark Division of Laboratory Animal Science and Welfare, Department of Pharmacology and Pathobiology
P Sandøe
Affiliation:
Centre for Bioethics and Risk Assessment, The Royal Veterinary and Agricultural University, 15 Bülowsvej, DK-1870 Frederiksberg C, Denmark Department of Animal Science and Animal Health
P F Johnsen
Affiliation:
Centre for Bioethics and Risk Assessment, The Royal Veterinary and Agricultural University, 15 Bülowsvej, DK-1870 Frederiksberg C, Denmark Department of Animal Science and Animal Health
J Lassen
Affiliation:
Centre for Bioethics and Risk Assessment, The Royal Veterinary and Agricultural University, 15 Bülowsvej, DK-1870 Frederiksberg C, Denmark Research Department of Human Nutrition
A Kornerup Hansen
Affiliation:
Division of Laboratory Animal Science and Welfare, Department of Pharmacology and Pathobiology
*
§ Contact for correspondence and requests for reprints: kda@kvl.dk
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Abstract

The welfare of transgenic animals is often not considered prior to their generation. However, we demonstrate here how a welfare risk assessment can be carried out before transgenic animals are created. We describe a risk assessment identifying potential welfare problems in transgenic pigs generated for future xeno-donation of organs. This assessment is based on currently available information concerning transgenic animal models in which one or more transgenes relevant to future xeno-donation have been inserted. The welfare risk assessment reveals that future xeno-donor pigs may have an increased tendency toward septicaemias, reduced fertility and/or impaired vision. The transgenic animal models used in generating hypotheses about the welfare of xeno-donor pigs can also assist in the testing of these hypotheses. To ensure high levels of welfare of transgenic animals, analogous risk assessments can be used to identify potential welfare problems during the early stages of the generation of new transgenic animals. Such assessments may form part of the basis on which licenses to generate new transgenic animals are granted to research groups.

Keywords

animal welfareorgan donorrisk assessmenttransgenesisxeno-donorxenotransplantation
Type
Research Article
Information
Animal Welfare , Volume 12 , Issue 2 , May 2003 , pp. 219 - 237
Copyright
© 2003 Universities Federation for Animal Welfare

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References

Andrea, C R and George, L W 1999 Surgical correction of periocular fat pad hypertrophy in pot-bellied pigs. Veterinary Surgery 28: 311–314CrossRefGoogle ScholarPubMed
Appleby, M C and Sandøe, P 2001 Philosophical debate on the nature of well-being: implications for animal welfare. Animal Welfare 11: 283–294Google Scholar
Avila, J L, Rojas, M and Towbin, H 1988 Serological activity against galactosyl-alpha(l-3)galactose in sera from patients with several kinetoplastida infections. Journal of Clinical Microbiology 26: 126–132CrossRefGoogle Scholar
Becht, E, Derouet, H and Ziegler, M 1991 Alloplastic ureter substitution and limitations in clinical application: a status analysis. Urologe A 30: 299–301Google ScholarPubMed
Bertschinger, H U and Fairbrother, J M 1999 Escherichia coli infections. In: Straw, B, D'Allaire, S, Mengeling, W L and Taylor, D J (eds) Diseases of Swine pp 431–468. Blackwell Science: Oxford, UKGoogle Scholar
Byrne, G W, McCurry, K R, Martin, M J, McClellan, S M, Platt, J L and Logan, J S 1997 Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage. Transplantation 63: 149–155CrossRefGoogle ScholarPubMed
Cargill, C F, Giesecke, P R, Heap, P A and Whyte, P B 1983 Bilateral cortical cataracts in sows. Australian Veterinary Journal 60: 312–313CrossRefGoogle ScholarPubMed
Chen, C G, Fisicaro, N, Shinkel, T A, Aitken, V, Katerelos, M, van Denderen, B J W, Tange, M J, Crawford, R J, Robins, A J, Pearse, M J and D'Apice, A J F 1996 Reduction in Gal-alpha 1,3-Gal epitope expression in transgenic mice expressing human H-transferase. Xenotransplantation 3: 69–75CrossRefGoogle Scholar
Chen, R H, Kadner, A, Mitchell, R N and Adams, D H 2000 Mechanism of delayed rejection in transgenic pig-to-primate cardiac xenotransplantation. Journal of Surgical Research 90: 119–125CrossRefGoogle ScholarPubMed
Cooper, D K C 1998 Xenoantigens and xenoantibodies. Xenotransplantation 5: 6–17CrossRefGoogle ScholarPubMed
Costa, C, Zhao, L, Decesare, S and Fodor, W L 1999 Comparative analysis of three genetic modifications designed to inhibit human serum-mediated cytolysis. Xenotransplantation 6: 6–16CrossRefGoogle ScholarPubMed
Cowan, P J, Aminian, A, Barlow, H, Brown, A A, Chen, C G, Fisicaro, N, Francis, DMA, Goodman, D J, Han, W R, Kurek, M, Nottle, M B, Pearse, M J, Salvaris, E, Shinkel, T A, Stainsby, G V, Stewart, A B and d'Apice, A J F 2000 Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagulopathy in non-immunosuppressed baboons. Transplantation 69: 2504–2515CrossRefGoogle Scholar
Cowan, P J, Shinkel, T A, Aminian, A, Romanella, M, Wigley, P L, Lonie, A J, Nottle, M B, Pearse, M J and d'Apice, A J F 1998a High-level co-expression of complement regulators on vascular endothelium in transgenic mice: CD55 and CD59 provide greater protection from human complement-mediated injury than CD59 alone. Xenotransplantation 5: 184–190CrossRefGoogle ScholarPubMed
Cowan, P J, Shinkel, T A, Witort, E J, Barlow, H, Pearse, M J and d'Apice, AJ 1996 Targeting gene expression to endothelial cells in transgenic mice using the human intercellular adhesion molecule 2 promoter. Transplantation 62: 155–160CrossRefGoogle ScholarPubMed
Cowan, P J, Tsang, D, Pedic, C M, Abbott, L R, Shinkel, T A, d'Apice, A J F and Pearse, M J 1998b The human ICAM-2 promoter is endothelial cell-specific in vitro and in vivo and contains critical Spl and GATA binding sites. The Journal of Biological Chemistry 273: 11737–11744CrossRefGoogle Scholar
CRT 2001 The Campaign for Responsible Transplantation http://www.crt-online.orgGoogle Scholar
Cutler, R S, Fahy, V A, Spicer, E M and Cronin, G M 1999 Preweaning mortality. In: Straw, B, D'Allaire, S, Mengeling, W L and Taylor, D J (eds) Diseases of Swine pp 985–1001. Blackwell Science: Oxford, UKGoogle Scholar
Davin, J-C, Malaise, M, Foidart, J and Mahieu, P 1987 Anti-a-galactosyl antibodies and immune complexes in children with Henoch-Schönlein purpura or IgA nephropathy. Kidney International 31: 1132–1139CrossRefGoogle ScholarPubMed
Doetschman, T 1999 Interpretion of phenotypes in genetically engineered mice. Laboratory Animal Science 49: 137–143Google Scholar
Duncan, J H 1996 Animal welfare defined in terms of feelings. Acta Agriculturae Scandinavica (Section A —Animal Science): 29-35 (Suppl 27)Google Scholar
Durant, J, Bauer, W and Gaskell, G 1998 Biotechnology in the Public Sphere. A European Sourcebook. The Science Museum: London, UKGoogle Scholar
El-Bab, M R F, Misk, N A, Hifny, A and Kaasem, A M 1982 Surgical anatomy of the lens in different domestic animals. Anatomia Histología Embryologia 11: 27–31CrossRefGoogle ScholarPubMed
Etienne-Decerf, J, Malaise, M, Mahieu, P and Winand, R 1987 Elevated anti-alpha-galactosyl antibody titres: a marker of progression in autoimmune thyroid disorders and in endocrine ophthalmopathy? Acta Endocrinologica (Copenhagen) 115: 67–74Google ScholarPubMed
Eurotransplant 2001 http://www.eurotransplant.orgGoogle Scholar
Ewbank, R 1985 Behavioral responses to stress in farm animals. In: Moberg, G P (ed) Animal Stress pp 71–79. American Physiological Society: Bethesda, MD, USACrossRefGoogle Scholar
Fodor, W L, Williams, B L, Matis, L A, Madri, J A, Rollins, S A, Knight, J W, Veländer, W and Squinto, S P 1994 Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. Proceedings of the National Academy of Sciences USA 91: 11153–11157CrossRefGoogle Scholar
Fraser, D, Weary, D M, Pajor, E A and Milligan, B N 1997 A scientific conception of animal welfare that reflects ethical concerns. Animal Welfare 6: 187–205Google Scholar
Frazier, O H 2000 Future directions of cardiac assistance. Seminars in Thoracic and Cardiovascular Surgery 12: 251–258CrossRefGoogle ScholarPubMed
Galili, U, Mandrel, R E, Hamadeh, R M, Shohet, S B and Griffiss, J M 1988 Interaction between human natural anti-a-galactosyl immunoglobulin G and bacteria of the human flora. Infection and Immunity 56: 1730–1737CrossRefGoogle ScholarPubMed
Galili, U, Rachmilewitz, E A, Peleg, A and Flechner, I 1984 A unique natural human IgG antibody with anti-alpha-galactosyl specificity. Journal of Experimental Medicine 160: 1519–1531CrossRefGoogle ScholarPubMed
Galili, U, Repik, P M, Anaraki, F, Mozdzanowska, K, Washko, G and Gerhard, W 1996 Enhancement of antigen presentation of influenza virus hemagglutinin by the natural human anti-Gal antibody. Vaccine 14: 321–328CrossRefGoogle ScholarPubMed
Garratty, G 1995 Blood-group antigens as tumor-markers, parasitic bacterial viral receptors, and their association with immunologically important proteins. Immunological Investigations 24: 213–232CrossRefGoogle ScholarPubMed
Glastonbury, J R 1977 Preweaning mortality in the pig: pathological findings in piglets dying between birth and weaning. Australian Veterinary Journal 53: 310–314CrossRefGoogle ScholarPubMed
Gonzalez, J, Ramirez, C, Seguel, X, Gutierrez, B, Manque, P, Porcile, P, Neira, I and Sagua, H 1995 Levels of anti-Gal antibodies in persons infected and non-infected with Trypanosoma cruzi: probably induced by bacteria and by the parasite. Boletin Chileno de Parasitologia 50: 3–9Google ScholarPubMed
Gordon, J W, Scangos, G A, Plotkin, D J, Barbosa, J A and Ruddle, F H 1980 Genetic transformation of mouse embryos by microinjection of purified DNA. Proceedings of the National Academy of Sciences USA 77: 7380–7384CrossRefGoogle ScholarPubMed
Gossler, A, Doetschman, T, Korn, R, Serfling, E and Kemler, R 1986 Transgenesis by means of blastocyst-derived embryonic stem cell lines. Proceedings of the National Academy of Sciences USA 83: 9065–9069CrossRefGoogle ScholarPubMed
Hamadeh, R M, Estabrook, M M, Zhou, P, Jarvis, G A and Griffiss, J M 1995 Anti-Gal binds to pili of Neisseria meningitidis: the immunoglobulin A isotype blocks complement-mediated killing. Infection and Immunity 63: 4900–4906CrossRefGoogle ScholarPubMed
Hamadeh, R M, Jarvis, G A, Zhou, P, Cotleur, A C and Griffiss, J M 1996 Bacterial enzymes can add galactose alpha 1,3 to human erythrocytes and create a senescence-associated epitope. Infection and Immunity 64: 528–534CrossRefGoogle ScholarPubMed
Hamadeh, R M, Jarvis, G A, Galili, U, Mandrell, R E, Zhou, P and Griffiss, M 1992 Human natural anti-gal IgG regulates alternative complement pathway activation on bacterial surfaces. The Journal of Clinical Investigation 89: 1223–1235CrossRefGoogle ScholarPubMed
Hammerberg, C, Schurig, G G and Ochs, D L 1989 Immunodeficiency in young pigs. American Journal of Veterinary Research 50: 868–874Google ScholarPubMed
Hansen, A K 1992 The aerobic bacterial flora of laboratory rats from a Danish breeding centre. Scandinavian Journal of Laboratory Animal Science 19: 59–68Google Scholar
Hansen, A K 1998 Microbiological quality of laboratory pigs. Scandinavian Journal of Laboratory Animal Science 25: 145–152Google Scholar
Ijzermans, J, Schraa, E O, Bonthuis, F, Yannnoutsos, N and Marquet, R L 1996 In vivo evaluation of human membrane cofactor protein in transgenic mice. Transplantation Proceedings 28: 671–672Google ScholarPubMed
Ikematsu, S, Kaneme, T, Ozawa, M, Yonezawa, S, Sato, E, Uehara, F, Obama, H, Yamamura, K and Muramatsu, T 1993 Transgenic mouse lines with ectopic expression of alpha-1,3- galactosyltransferase — production and characteristics. Glycobiology 3: 575–580CrossRefGoogle ScholarPubMed
ITCS 2001 International Transplant Coordinators Society http://www.itcs.orgGoogle Scholar
Julvez, J, Vannier, P and Wadham, L 2000 Microbiological hazards of xenotransplantation. I: Doubts and convictions relating to the risk of xenozoonosis. Pathologie Biological (Paris) 48: 429–435Google Scholar
Koba, Y and Tanida, H 1999 How do miniature pigs discriminate between people? The effect of exchanging cues between a non-handler and their familiar handler on discrimination. Applied Animal Behaviour Science 61: 239–252CrossRefGoogle Scholar
Koike, C, Kannagi, R, Takuma, Y, Akutsu, F, Hayashi, S, Hiraiwa, N, Kadomatsu, K, Muramatsu, T, Yamakawa, H, Nagai, T, Kobayashi, S, Okada, H, Nakashima, I, Uchida, K, Yokoyama, I and Takagi, H 1996 Introduction of alpha(l,2)-fucosyltransferase and its effect on alpha-Gal epitopes in transgenic pig. Xenotransplantation 3: 81–86CrossRefGoogle Scholar
Lai, L 2002 Production of alpha-l,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 295: 1089–1092CrossRefGoogle Scholar
LaTemple, D C and Galili, U 1998 Adult and neonatal anti-Gal response in knockout mice for αl,3galactosyltransferase. Xenotransplantation 5: 191–196CrossRefGoogle Scholar
Malaise, M G, Davin, J C, Mahieu, P R and Franchimont, P 1986 Elevated antigalactosyl antibody titers reflect renal injury after gold or D-penicillamine in rheumatoid arthritis. Clinical Immunology and Immunopathology 40: 356–364 [Published erratum appears in Clinical Immunology and Immunopathology 41: 303]CrossRefGoogle ScholarPubMed
Nielsen, K, Nielsen, R, Nansen, P and Andersen, S 1973 Isoimmune purpura thrombocytopenica in piglets. Folia Veterinaria Latina 3: 32–51Google ScholarPubMed
Nielsen, N C, Riising, H J, Larsen, J L, Bille, N and Svendsen, J 1975 Preweaning mortality in pigs. 5: Acute septicaemias. Nordic Veterinary Medicine 27: 129–139Google ScholarPubMed
Nuffield Council on Bioethics 1996 Animal-to-human transplants: the ethics of xenotransplantation. Nuffield Council on Bioethics: London, UKGoogle Scholar
Olsson, K 2000 Xenotransplantation and animal welfare. Transplantation Proceedings 32: 1172–1173CrossRefGoogle ScholarPubMed
Oriol, R, Ye, Y, Koren, E and Cooper, D K C 1993 Carbohydrate antigens of pig-tissues reacting with human natural antibodies as potential targets for hyperacute vascular rejection in pig-to-man organ xenotransplantation. Transplantation 56: 1433–1442CrossRefGoogle ScholarPubMed
Pearse, M J, Cowan, P J, Shinkel, T A, Chen, C G and d'Apice, A J 1999 Anti-xenograft immune responses in alpha 1,3-galactosyltransferase knockout mice. Subcellular Biochemistry 32: 281–310Google Scholar
Pocard, M 1999 Origin of animal experimentation legislation in the 19th century. Annales de Chirurgie 53: 627–631Google ScholarPubMed
Pursel, V G, Hammer, R E, Bolt, D J, Palmiter, R D and Brinster, R L 1990 Integration, expression and germ-line transmission of growth-related genes in pigs. Journal of Reproduction and Fertility 41: 77–78 (Suppl)Google ScholarPubMed
Reed, D J, Lin, X, Thomas, T D, Birks, C W, Tang, J and Rother, R P 1997 Alteration of glycosylation renders HIV sensitive to inactivation by normal human serum. Journal of Immunology 159: 4356–4361CrossRefGoogle ScholarPubMed
Repik, P M, Strizki, J M and Galili, U 1994 Differential host-dependent expression of alpha-galactosyl epitopes on viral glycoproteins: a study of Eastern equine encephalitis virus as a model. Journal of Genetics and Virology 75(Pt 5): 1177–1181CrossRefGoogle ScholarPubMed
Rijkers, T, Peetz, A and Rüther, U 1994 Insertional mutagenesis in transgenic mice. Transgenic Research 3: 203–215CrossRefGoogle ScholarPubMed
Rollin, B E 1995 Genetic engineering and animal telos. In: Rollin, B E (ed) The Frankenstein Syndrome pp 171–176. Cambridge University Press: New York, USACrossRefGoogle Scholar
Rosengard, A M, Cary, N R, Langford, G A, Tucker, A W, Wallwork, J and White, D J 1995 Tissue expression of human complement inhibitor, decay-accelerating factor, in transgenic pigs: a potential approach for preventing xenograft rejection. Transplantation 59: 1325–1333CrossRefGoogle ScholarPubMed
Shapiro, B M and Eddy, E M 1980 When sperm meets egg: biochemical mechanisms of gamete interaction. International Review of Cytology 66: 257–302CrossRefGoogle ScholarPubMed
Sharma, A, Okabe, J, Birch, P, McClellan, S B, Martin, M J, Platt, J L and Logan, J S 1996 Reduction in the level of Gal(al,3)Gal in transgenic mice and pigs by the expression of an a(l,2)fucosyltransferase. Proceedings of the National Academy of Sciences USA 93: 7190–7195CrossRefGoogle Scholar
Shur, B D and Hall, N G 1982a A role for mouse sperm surface galactosyltransferase in sperm binding to the egg zona pellucida. Journal of Cell Biology 95: 574–579CrossRefGoogle Scholar
Shur, B D and Hall, N G 1982b Sperm surface galactosyltransferase activities during in vitro capacitation. Journal of Cell Biology 95: 567–573CrossRefGoogle ScholarPubMed
Stafleu, F R, Grommers, F L and Vorstenbosch, J 1996 Animal welfare: evolution and erosion of a moral concept. Animal Welfare 5: 225–234Google Scholar
Takeuchi, Y, Porter, C D, Strahan, K M, Preece, A F, Gustafsson, K, Cosset, F L, Weiss, R A and Collins, M K 1996 Sensitization of cells and retroviruses to human serum by (alpha 1-3) galactosyltransferase. Nature 379: 85–88CrossRefGoogle ScholarPubMed
Tanemura, M and Galili, U 2000 Differential expression of α-Gal epitopes on pig and mouse organs. Transplantation Proceedings 32: 843CrossRefGoogle ScholarPubMed
Tannenbaum, J 1991 Ethics and animal welfare: the inextricable connection. Journal of the American Veterinary Medical Association 198: 1360–1376Google ScholarPubMed
Tearle, R G, Tange, M, Zannettino, Z L, Katerelos, M, Shinkel, T A, d'Apice, A J F, Lonie, A J, Lyons, I, Nottle, M B, Cox, T, Becker, C, Peura, A M, Wigley, P L, Crawford, R J, Robins, A J and Pearse, M J 1996 The α-l,3-galactosyltransferase knockout mouse. Transplantation 61: 13–19CrossRefGoogle Scholar
Thall, A, Etienne-Decerf, J, Winand, R J and Galili, U 1991a The alpha-galactosyl epitope on mammalian thyroid cells. Acta Endocrinología (Copenhagen) 124: 692–699Google ScholarPubMed
Thall, A, Etienne-Decerf, J, Winand, R J and Galili, U 1991b The α-galactosyl epitope on human normal and autoimmune thyroid cells. Autoimmunity 19: 81–87CrossRefGoogle Scholar
Thall, A, Malý, P and Lowe, J B 1995 Oocyte Galal,3Gal epitopes implicated in sperm adhesion to the zona pellucida glycoprotein ZP3 are not required for fertilization in the mouse. The Journal of Biological Chemistry 270: 21437–21440CrossRefGoogle Scholar
Towbin, H, Rosenfelder, G, Wieslander, J, Avila, J L, Rojas, M, Szarfman, A, Esser, K, Nowack, H and Timpl, R 1987 Circulating antibodies to mouse laminin in Chagas disease, American cutaneous leishmaniasis, and normal individuals recognize terminal galactosyl(alpha 1-3)-galactose epitopes. Journal of Experimental Medicine 166: 419–432CrossRefGoogle ScholarPubMed
Treniont-Lukats, I W, Avila, J L, Hernandez, D, Vasquez, J, Teixeira, G M and Rojas, M 1997 Antibody levels against alpha-galactosyl epitopes in sera of patients with squamous intraepithelial lesions and early invasive cervical carcinoma. Gynecology and Oncology 64: 207–212CrossRefGoogle Scholar
UNOS 2001 United Network for Organ Sharing http://www.unos.orgGoogle Scholar
van Denderen, B J W, Salvaris, E, Romanella, M, Aminian, A, Katerelos, M, Tange, M J, Pearse, M J and D'Apice, A J F 1997 Combination of decay-accelerating factor expression and alpha 1,3- galactosyltransferase knockout affords added protection from human complement-mediated injury. Transplantation 64: 882–888CrossRefGoogle Scholar
van der Meer, M, Baumans, V and van Zutphen, LFM 1996 Transgenic animals: what about their well-being? Scandinavian Journal of Laboratory Animal Science 23: 287–290Google Scholar
Vanderpool, H Y 1998 Critical ethical issues in clinical trials with xeno transplants. The Lancet 351: 1347–1349CrossRefGoogle Scholar
Wetter, L A, Hamadeh, R M, Griffiss, J M, Oesterle, A, Aagaard, B and Way, L W 1994 Differences in outer membrane characteristics between gallstone-associated bacteria and normal bacterial flora. Lancet 343: 444–448CrossRefGoogle ScholarPubMed