Hostname: page-component-586b7cd67f-r5fsc Total loading time: 0 Render date: 2024-11-25T04:19:38.513Z Has data issue: false hasContentIssue false
  • English
  • Français

Microbiological Hazards Related to Xenotransplantation of Porcine Organs Into Man

Published online by Cambridge University Press:  02 January 2015

Dominic C. Borie ,
Donald V. Cramer ,
Luu Phan-Thanh ,
Jean Christophe Vaillant ,
Jean Louis Bequet ,
Leonard Makowka  and
Laurent Hannoun
Dominic C. Borie
Affiliation:
Department of Hepato-Biliary Surgery and Liver Transplantation, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Donald V. Cramer
Affiliation:
Transplantation Biology Research Laboratory, St. Vincent Medical Center, Los Angeles, California
Luu Phan-Thanh
Affiliation:
Infectious Diseases and Immunology, PII, Institut National de la Recherche Agronomique, Nouzilly, France
Jean Christophe Vaillant
Affiliation:
Department of Hepato-Biliary Surgery and Liver Transplantation, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Jean Louis Bequet
Affiliation:
Charles River Laboratories, Saint-Aubin-Les-Elbeuff, France
Leonard Makowka
Affiliation:
Transplantation Biology Research Laboratory, St. Vincent Medical Center, Los Angeles, California
Laurent Hannoun
Affiliation:
Department of Hepato-Biliary Surgery and Liver Transplantation, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Get access Rights & Permissions [Opens in a new window]

Abstract

Pigs are emerging as the most likely providers of genetically engineered organs and cells for the purpose of clinical xenotransplantation. Introduction of clinical trials has been delayed primarily by uncertainties regarding the risk of swine pathogen transmission that could harm the recipient. The concern that xenotransplantation carries the potential for a new epidemic has been highlighted by recent experiences with both bovine spongiform encephalopathy and human immunodeficiency diseases.

As clinical trials have been postponed and xenotransplantation teams are working actively to gather data for an estimation of the risk, this review provides the reader with a state-of-the-art estimation of the microbiological hazards related to xenotransplantation of porcine organs to man. Particular emphasis is put on viral and retroviral hazards. Both current diagnostic tools and those under development are described, along with breeding strategies to provide donor animals that would not put the recipient or the general population at risk

Type
Emerging Infectious Diseases
Information
Infection Control & Hospital Epidemiology , Volume 19 , Issue 5 , May 1998 , pp. 355 - 365
Copyright
Copyright © The Society for Healthcare Epidemiology of America 1998

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

1. Browne, BJ, Kahan, BD. Transplantation 1994: the year in review. Clinical Transplants 1994;317–340.Google Scholar
2. Pierce, GA, Kauffman, HM, Ellison, MD, Edwards, EB, Klein, DH, Wolf, JS, et al. UNOS scientific registry: present and future. Transplant Proc 1996;28:2355–2357.Google Scholar
3. Hammer, C. Evolutionary, physiological and immunological considerations in defining a suitable donor for man. In: Cooper, DKC, Kemp, E, Reemstma, K, White, DJG, eds. Xenotransplantation. The Transplantation of Organs and Tissues Between Species. Berlin, Germany: Springer-Verlag; 1991:429–438.CrossRefGoogle Scholar
4. Michaels, MG, Simmons, RL. Xenotransplant-associated zoonoses. Transplantation 1994;57:1–7.Google Scholar
5. Michaels, MG, McMichael, JP, Brasky, K, Kalter, S, Peters, RL, Starzl, TE, et al. Screening donors for xenotransplantation. The potential for xeno-zoonoses. Transplantation 1994;57:1462–1465.Google Scholar
6. Blanchard, D, Thibaudeau, K, Soulillou, JP. Porcine antigenic targets for human natural antibodies. Xeno 1995;3:68–71.Google Scholar
7. Cooper, DKC, Ye, Y, Rolf, LL Jr, Zuhdi, N. The pig as a potential organ donor for man. In: Cooper, DKC, Kemp, E, Reemstma, K, White, DJG, eds. Xenotransplantation. The Transplantation of Organs and Tissues Between Species. Berlin: Springer-Verlag; 1991:481–500.Google Scholar
8. Pensaert, MB. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989.Google Scholar
9. Acha, PN, Szyfres, B. Zoonoses and Communicable Diseases Common to Man and Animals. 2nd ed. Paris, France: Office Intl des Epizooties; 1987.Google Scholar
10. Lautner, B, Friendship, RM. Human health in swine veterinary practice. Compendium on Continuing Education for the Practicing Veterinarian. 1992;14:99–101.Google Scholar
11. Fishman, JA. Miniature swine as organ donors for man: strategies for prevention of xenotransplant-associated infections. Xenotransplantation 1994;1:47–57.Google Scholar
12. Eiseman, B, Liem, DS, Raffucci, F. Heterologous liver perfusion in treatment of hepatic failure. Ann Surg 1965;162:329–345.Google Scholar
13. Chari, S, Collins, BH, Magee, JC, DiMaio, JM, Kirk, AD, Harland, RC, et al. Treatment of hepatic failure with ex vivo pig liver perfusion followed by liver transplantation. N Engl J Med 1994;331:234–237.Google Scholar
14. Breimer, ME, Björck, S, Svalander, CT, Bengtsson, A, Rydberg, L, Lie-Karlsen, K, et al. Extracorporeal (“ex vivo”) connection of pig kidneys to humans, I: clinical data and studies of platelet destruction. Xenotrans- plantation 1996;3:328–339.CrossRefGoogle ScholarPubMed
15. Reemtsma, K, Benvenisty, AI. Experience with clinical kidney xenotrans-plantation. In: Cooper, DKC, Kemp, E, Reemstma, K, White, DJG, eds. Xenotransplantation. The Transplantation of Organs and Tissues Between Species. Berlin, Germany: Springer-Verlag; 1991: 531–540.Google Scholar
16. Groth, CG, Korsgren, O, Tibell, A, Tollemar, J, Möller, E, Bolinder, J, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 1994;344:1402–1404.Google Scholar
17. Makowka, L, Cramer, DV, Hoffman, A, Breda, M, Sher, L, Eiras-Hreha, G, et al. The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure. Transplantation 1995;59:1654–1659.Google Scholar
18. Kapperud, G. Yersinia enterolitica in food hygiene. Int J Food Microbiol 1991;12:53–66.Google Scholar
19. Franke, S, Harmsen, D, Caprioli, A, Pierard, D, Wieler, L, Karch, H. Clonal relatedness of Shiga-like toxin-producing Escherichia coli 0101 strains of human and porcine origin. J Clin Microbiol 1995;33:3174–3178.Google Scholar
20. Yuen, KY, Seto, WH, Choi, CH, Ng, W, Ho, SW, Chau, PY. Streptococcus zooepidemicus (Lancefield group C) septicemia in Hong Kong. J Infect 1990;21:241–250.Google Scholar
21. Robicsek, F, Hoffman, PC, Masters, TN, Daugherty, HK, Cook, JW, Selle, JG, et al. Rapidly growing non-tuberculous mycobacteria: a new enemy of the cardiac surgeon. Ann Thorac Surg 1988;46:703–710.Google Scholar
22. Wreghitt, TG, Hakim, M, Gray, JJ, Balfour, AH, Stovin, PG, Stewart, S, et al. Toxoplasmosis in heart and lung transplant recipients. J Clin Pathol 1989;42:194–199.Google Scholar
23. Ho, M, Dummer, S, Peterson, PK, Simmons, RL. Infections in solid organ transplant recipients. In: Mandell, GL, Gordon Douglas, R Jr, Bennett, JE, eds. Principles and Practice of Infectious Diseases. 3rd ed. New York, NY: Churchill Livingstone; 1990:2294–2303.Google Scholar
24. Keusch, GT, Hamer, D, Joe, A, Kelley, M, Griffiths, J, Ward, H. Cryptosporidia: who is at risk? Schweiz Med Wochenschr 1995;125:899–908.Google Scholar
25. Starzl, TE, Fung, J, Tzakis, A, Todo, S, Demetris, AJ, Marino, IR, et al. Baboon-to-human liver transplantation. Lancet 1993;341:65–71.Google Scholar
26. Michaels, MG, Lanford, R, Demetris, AJ, Chavez, D, Brasky, K, Fung, J, et al. Lack of susceptibility of baboons to infection with hepatitis B virus. Transplantation 1996;61:350–351.Google Scholar
27. Gravel, M, London, WT, Rodriguez, M, Palmer, AE, Hamilton, RS. Simian hemorrhagic fever (SHF): new virus isolate from a chronically infected patas monkey. J Virol 1980;51:99–106.Google Scholar
28. Palmer, AE, Allen, AM, Tauraso, NM, Shelekov, A. Simian hemorrhagic fever, I: clinical and epizootiologic aspects of an outbreak among quarantined monkeys. Am J Trop Med Hyg 1968;17:404–412.Google Scholar
29. Holmes, GP, Chapman, LE, Stewart, JA, Strauss, SE, Hilliard, JK, Davenport, DS. Guidelines for the prevention and treatment of B-virus infections in exposed persons. Clin Infect Dis 1995;20:421–439.CrossRefGoogle ScholarPubMed
30. Mengeling, WL, Brockmeier, SL, Lager, KM, Vorwald, AC. The role of biotechnologically engineered vaccines and diagnostics in pseudorabies (Aujeszky's disease) eradication strategies. Vet Microbiol 1997;55:49–60.Google Scholar
31. Baumeister, J, Klupp, BG, Mettenleiter, TC. Pseudorabies virus and equine herpesvirus 1 share a nonessential gene which is absent in other herpesvirus and located adjacent to a highly conserved gene cluster. J Virol 1995;69:5560–5567.Google Scholar
32. Subramanian, G, LeBlanc, RA, Wardley, RC, Fuller, AO. Defective entry of herpes simplex virus type 1 and 2 into porcine cells and lack of infection in infant pigs indicate species tropism. J Gen Virol 1995;76:2375–2379.Google Scholar
33. Dangler, CA, Henderson, LM, Deaver, RE, Bowman, LA. Recovery of Aujeszky's disease virus recombinants from experimentally co-infected swine. Acta Vet Hung 1994;42:209–212.Google Scholar
34. Edington, N. Porcine cytomegalovirus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:65–70.Google Scholar
35. Tajima, T, Hironao, T, Kajikawa, T, Kawamura, H. Application of enzyme-linked immunosorbent assay for the seroepizootiological survey of antibodies against porcine cytomegalovirus. J Vet Med Sci 1993;55:421–424.Google Scholar
36. Watt, RG, Plowright, W, Sabo, A, Edington, N. A sensitive system for the virus of porcine inclusion body rhinitis (cytomegaly inclusion disease). Res Vet Sci 1973;14:119–121.Google Scholar
37. Derbyshire, JB. Porcine adenovirus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:73–80.Google Scholar
38. Kiss, I, Matiz, K, Allard, A, Wadell, G, Benko, M. Detection of homologous DNA sequences in animal adenoviruses by polymerase chain reaction. Acta Vet Hung 1996;44:243–251.Google Scholar
39. Derbyshire, JB, Collins, AP. Virological studies on an experimental minimal disease herd of pigs. Br Vet J 1971;127:436–441.Google Scholar
40. Kadoi, K. Beneficial use of inactivated porcine adenovirus vaccine and antibody response of young pigs. New Microbiologica 1997;20:89–91.Google ScholarPubMed
41. Debouck, P. Porcine rotavirus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:97–109.Google Scholar
42. Deverdier Klingenberg, K, Esfandiari, J. Evaluation of a one-step test for rapid, in practice detection of rotavirus in farm animal. Vet Rec 1996;138:393–395.Google Scholar
43. Bridger, JC, Pedley, S, McCrae, MA. Group C rotaviruses in humans. J Clin Microbiol 1986;23:760–763.Google Scholar
44. Castrucci, G, Ferrari, M; Frigeri, F, Traldi, V, Angelillo, V. A study on neonatal calf diarrhea induced by rotavirus. Comp Immunol Microbiol Infect Dis 1994;17:321–331.Google Scholar
45. Follet, EAC, Desselberger, U. Co-circulation of different rotavirus strains in a local outbreak of infantile gastro-enteritis: monitoring by rapid and sensitive nucleic acid analysis. J Med Virol 1983;11:39–52.Google Scholar
46. Joo, HS. Japanese encephalitis virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:131–136.Google Scholar
47. Fujisaki, Y, Sugimori, T, Morimoto, T, Miura, Y, Kawakami, Y, Nakano, K. Immunization of pigs with the attenuated strain S-strain of Japanese encephalitis virus. National Institute of Animal Health Quarterly 1975;15:55–60.Google Scholar
48. Carbrey, EA. Vesicular stomatitis virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:211–218.Google Scholar
49. Afshar, A, Shakarchi, NH, Dulac, GC. Development of a competitive enzyme-linked immunosorbent assay for detection of bovine, ovine, porcine, and equine antibodies to vesicular stomatitis virus. J Clin Microbiol 1993;31:1860–1865.Google Scholar
50. Baer, GM. Rabies virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:219–222.Google Scholar
51. Blenden, DC, Creech, W, Torres-Angel, MJ. Use of immunofluorescence examination to detect rabies virus antigen in the skin of humans with clinical encephalitis. J Infect Dis 1986;154:698–701.Google Scholar
52. Mann, JA, Sellers, RF. Foot-and-mouth disease virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:251–258.Google Scholar
53. O'Donnell, VK, Boyle, DB, Sproat, K, Fondevila, NA, Forman, A, Schudel, AA, et al. Detection of antibodies against foot-and-mouth disease virus using a liquid-phase blocking sandwich ELISA (LPBE) with a bioengi-neered 3D protein. J Vet Diagn Invest 1996;8:143–150.Google Scholar
54. Vangrysperre, W, De Clercq, K. Rapid and sensitive polymerase chain reaction based detection and typing of foot-and-mouth disease virus in clinical samples and cell culture isolates, combined with a simultaneous differentiation with other genomically and/or symptomatically related viruses. Arch Virol 1996;141:331–344.Google Scholar
55. Rieder, E, Baxt, B, Lubroth, J, Mason, PW. Vaccines prepared from chimeras of foot-and-mouth disease virus (FMDV) induce neutralizing antibodies and protective immunity to multiple serotypes of FMDV. J Virol 1994;68:7092–7098.Google Scholar
56. Hedger, RS, Mann, JA. Swine vesicular disease virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:241–250.Google Scholar
57. Marquardt, O, Ohlinger, VF. Differential diagnosis and genetic analysis of the antigenically related swine vesicular disease virus and Coxsackie viruses. J Virol Methods 1995;53:189–199.Google Scholar
58. Brocchi, E, Berlinzani, A, Gamba, D, De Simone, F. Development of two novel monoclonal antibody-based ELISAs for the detection of antibodies and the identification of swine isotypes against swine vesicular disease virus. J Virol Methods 1995;52:155–167.Google Scholar
59. Lin, F, Mackay, DK, Knowles, NJ. Detection of swine vesicular disease virus RNA by reverse transcription-polymerase chain reaction. J Virol Methods 1997;65:111–121.Google Scholar
60. Acland, HM. Encephalomyocarditis virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:259–264.Google Scholar
61. Bachmann, PA. Swine influenza virus. In: Pensaert, MB, ed. Virus Infections of Porcines. Amsterdam, The Netherlands: Elsevier Science Publishers BV; 1989:193–207.Google Scholar
62. Webster, RG, Bean, WJ, Gorman, OT, Chambers, TM, Kawaoka, Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992;56:152–179.Google Scholar
63. Rekik, MR, Arora, DJS, Dea, S. Genetic variation in swine influenza virus A isolate associated with proliferative and necrotizing pneumonia in pigs. J Clin Microbiol 1994;32:515–518.CrossRefGoogle Scholar
64. Shortridge, KF. Pandemic influenza: a zoonosis? Semin Respir Infect 1992;7:11–25.Google Scholar
65. Webster, RG, Sharp, GB, Claas, ECJ. Interspecies transmission of influenza viruses. Am J Respir Crit Care Med 1995;152:525–530.Google Scholar
66. Renegar, KB. Influenza virus infections and immunity: a review of human and animal models. Lab Anim Sci 1992;42:222–232.Google ScholarPubMed
67. McKinney, WP, Volkert, P, Kaufman, J. Fatal swine influenza pneumonia during late pregnancy. Arch Intern Med 1990;150:213–214.CrossRefGoogle ScholarPubMed
68. Rota, PA, Rocha, EP, Harmon, MW, Hinshaw, VS, Sheerar, MG, Kawaoka, Y, et al. Laboratory characterization of a swine influenza virus isolated from a fatal case of human influenza. J Clin Microbiol 1989;27:1513–1516.Google Scholar
69. Wells, DL, Hopfensperger, DJ, Arden, NH, Harmon, MW, Davis, JP, Tipple, MA, et al. Swine influenza virus infection. Transmission from ill pigs to humans at a Wisconsin agricultural fair and subsequent probable person-to-person transmission. JAMA 1991;265:478–481.Google Scholar
70. Schorr, E, Wentworth, D, Hinshaw, VS. Use of polymerase chain reaction to detect swine influenza virus in nasal swab specimens. Am J Vet Res 1994;55:952–956.Google Scholar
71. Doolittle, RF, Feng, DF. Tracing the origin of retroviruses. Curr Top Microbiol Immunol 1992;176:195–211.Google Scholar
72. Katz, RA, Skalka, AM. Generation of diversity in retroviruses. Annu Rev Genet 1990;24:409–445.Google Scholar
73. Coffin, JM. Genetic diversity and evolution of retroviruses. Curr Top Microbiol Immunol 1992;176:143–164.Google Scholar
74. Frazier, ME. Evidence for retrovirus in miniature swine with radiation-induced leukemia or metaplasia. Arch Virol 1985;83:83–97.Google Scholar
75. Bouillant, AM, Greig, AS, Lieber, MM, Todaro, GJ. Type C retrovirus production by a continuous line of pig oviduct cells (PFT). J Gen Virol 1975;27:173–180.Google Scholar
76. Todaro, GJ, Benveniste, RE, Lieber, MM, Sherr, CJ. Characterization of a type C virus released from the porcine cell line PK(15). Virology 1974;58:65–74.Google Scholar
77. Sandstrom, H, Veijalaineine, P, Moennig, V, Hunsmann, G, Schwarz, H, Schafer, W. C-type particles produced by a permanent cell line from leukemic pig, I: origin and properties of the host cells and some evidence for the occurrence of C-type-like particles. Virology 1974;57:175–178.Google Scholar
78. Benveniste, RE, Todaro, GJ. Evaluation of type C viral genes: preservation of ancestral murine type C viral sequences in pig cellular DNA. Proc Natl Acad Sci USA 1975;72:4090–4094.Google Scholar
79. Lieu, CI. The experimental infection of pregnant guinea pigs with porcine enterovirus SMEDIA strain. Taiwan Journal of Veterinary Medicine and Animal Husbandry 1976;28:1–14.Google Scholar
80. Patience, C, Takeuchi, Y, Weiss, RA. Infection of human cells by an endogenous retrovirus of pigs. Nature Medicine 1997;3:282–286.Google Scholar
81. Fishman, JA. Preventing infections in xenotransplantation: xenosis from miniature swine. Xeno 1995;3:72–77.Google Scholar
82. Johnson, ES. Poultry oncogenic retroviruses and humans. Cancer Detection and Prevention 1994;18:9–30.Google Scholar
83. Weber, T, Hunsmann, G, Stevens, W, Fleming, AF. Human retroviruses. Baillieres Clin Haematol 1992;2:273–314.Google Scholar
84. Chapman, LE, Folks, TM, Salomon, DR, Patterson, AP, Eggerman, TE, Noguchi, PD. Xenotransplantation and xenogeneic infections. N Engl J Med 1995;333:1498–1501.Google Scholar
85. Phan-Thanh, L, Kaeffer, B, Bottreau, E. Porcine retrovirus: optimal conditions for its biochemical detection. Arch Virol 1992;123:255–265.Google Scholar
86. Hoopes, CW, Platt, JL. Molecular screening of xenodonor genomes for species-specific endogenou retroviral DNA sequences. Transplantation Proceedings 1997;29:897–898.Google Scholar
87. Prusiner, S. The prion diseases. Sci Am 1995;272:30–37.Google Scholar
88. Collinge, J, Palmer, MS, Sidle, KC, Hill, AF, Gowland, I, Meads, J, et al. Unai-tered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 1995;378:779–783.Google Scholar
89. Schatzl, HM, Da-Costa, M, Taylor, L, Cohen, FE, Prusiner, SB. Prion protein gene variation among primates. J Mol Biol 1995;245:362–374.Google Scholar
90. Collinge, J, Rossor, M. A new variant of prion disease. Lancet 1996;347:916–917.Google Scholar
91. Diringer, H. Proposed link between transmissible spongiform encephalopathies of man and animals. Lancet 1995;346:1208–1210.Google Scholar
92. Martin, T, Hughes, S, Hughes, K, Dawson, M. Direct sequencing of PCR amplified pig PrP genes. Biochim Biophys Acta 1995;1270:211–214.CrossRefGoogle ScholarPubMed
93. Creange, A, Gray, F, Cesaro, P, Adle-Biassette, H, Duroux, C, Cherqui, D, et al. Creutzfeldt-Jakob disease after liver transplantation. Ann Neurol 1995;38:269–272.Google Scholar
94. Ye, Y, Niekrasz, M, Kosanke, S, Welsh, R, Jordan, HE, Fox, JC, et al. The pig as a potential organ donor for man. A study of potentially transferable disease from donor pig to recipient man. Transplantation 1994;57:694–703.Google Scholar
95. Miniats, OP. Production of germ-free animals; part II: farm animals. In: Coates, ME, Gustafsson, BE, eds. The Germ-Free Animal in Biomedical Research. London, England: Laboratory Animals Ltd; 1984:49–60.Google Scholar
96. Cariolet, R, Tillon, JP. La production de porcelets exempts d'organismes pathogènes spécifiques (EOPS) à la station de pathologie porcine de Ploufragan. Sciences et Techniques des Animaux de Laboratoire 1978;3:213–225.Google Scholar
97. Cariolet, R. Bilan de 10 années d'utilisation de porcs exempts d'organismes pathogènes spécifiques (EOPS) à la station de pathologie porcine de Ploufragan. Journées de la Recherche Porcine en France 1986;18:321–330.Google Scholar
98. Makowka, L, Cramer, DV. The pathogenesis of xenograft rejection. In: Hackel, B, Aubuchon, J, eds. Advances in Transplantation. Bethesda, MD: American Association of Blood Banks; 1993:93–112.Google Scholar
99. Borie, DC, Poynard, T, Hannoun, L. Xénotransplantation chez l'homme, I: immunobiologie du rejet xénogénique. Gastroenterol Clin Biol 1996;20:972–981.Google Scholar
100. Borie, DC, Poynard, T, Hannoun, L. Xénotransplantation chez l'homme, II: contrôle du rejet et application à la xénotransplantation de foie de porc chez l'homme. Gastroenterol Clin Biol 1996;20:982–990.Google Scholar