Xenotransplantation: An Overview

  • Rizwan A. Manji
  • Jacqueline S. Manji
  • Ray V. Rajotte
  • Arvind Koshal
Part of the Progress in Experimental Cardiology book series (PREC, volume 10)


Interest in xenotransplantation has increased significantly as a possible response to the critical organ shortage crisis that exists in clinical transplantation today. The pig has been suggested to be the most suitable animal for human xenotransplantation, however, many barriers still exist to the clinical application of xenotransplantation.

This review takes a brief look at the history of clinical xenotransplantation, the choice of organ donor, the obstacles to xenotransplantation and attempts to overcome them. Xenografted organs will likely be used as a bridge to allotransplantation before being used as full blown replacements for human organs. There is much progress that has been made, but still much to do. With perseverance and good science, solutions are likely to be found.

Key words

xenotransplantation rejection alpha-Gal antibody pig 


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  1. 1.
    Carrel A. 1983. Landmark article, Nov 14, 1908: Results of the transplantation of blood vessels, organs and limbs. JAMA 250:944–953.PubMedCrossRefGoogle Scholar
  2. 2.
    Carrel A. 1992. The preservation of tissues and its applications in surgery. 1912. Clin Orthop 2–8.Google Scholar
  3. 3.
    Gunn A, Medawar P. 1971. Studies on the induction of transplantation tolerance at low zones of dosage. Br J Surg 58:858.PubMedGoogle Scholar
  4. 4.
    Burnet FM. 1991. The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine, 1960. Immunologic recognition of self. Scand J Immunol 33:3–13.PubMedCrossRefGoogle Scholar
  5. 5.
    Medawar P. 1981. The Nobel awards for medicine or physiology. Nature 289:345.PubMedCrossRefGoogle Scholar
  6. 6.
    Merion RM, White DJ, Thiru S, Evans DB, Calne RY. 1984. Cyclosporine: five years’ experience in cadaveric renal transplantation. N Engl J Med 310:148–154.PubMedCrossRefGoogle Scholar
  7. 7.
    International Figures on Organ Donation and Transplantation (1999). 1999. (Online). Council of Europe, Scholar
  8. 8.
    Cooper DK, Lanza RP. 2000. Xeno: the promise of transplanting animal organs into humans. Ed. 1–274. New York: Oxford University Press.Google Scholar
  9. 9.
    Meeting the organ shortage (1999). 1999. (Online). Council of Europe. Scholar
  10. 10.
    Mihaylov D, Verkerke GJ, Rakhorst G. 2000. Mechanical circulatory support systems—a review. Technol Health Care 8:251–266.PubMedCrossRefGoogle Scholar
  11. 11.
    Mussivand T. 1999. Mechanical circulatory devices for the treatment of heart failure. J Card Surg 14:218–228.PubMedCrossRefGoogle Scholar
  12. 12.
    Organ Farm—Frontline. 2001. (Online). PBS online—Frontline. Scholar
  13. 13.
    Markmann JF, Barker CF. 1994. Current Problems in Surgery. Ed. SAJ Wella, New York: Mosby.Google Scholar
  14. 14.
    Reemtsma K. 1964. Renal Heterotransplantation in Man. Annals of Surgery 160:384.PubMedCrossRefGoogle Scholar
  15. 15.
    Starzl TE. 1964. Renal Heterotransplantation from Baboon to Man: Experience with 6 Cases. Transplantation 2:752.PubMedCrossRefGoogle Scholar
  16. 16.
    Taniguchi H, Cooper DKC. 1997. Clinical xenotransplantation—A brief review of the world experience. In: Xenotransplantation: The Transplantation of Organs and Tissues Between Species. Ed. DKC Cooper, E Kemp, JL Piatt, DJG White, 776–785. New York: Springer.Google Scholar
  17. 17.
    Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. 1985. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA 254:3321–3329.PubMedCrossRefGoogle Scholar
  18. 18.
    Makowka L, Wu GD, Hoffman A, Podesta L, Sher L, Tusa PJ, Breda M, Chapman FA, Cosenza C, Yasunga C. 1994. Immunohistopathologic lesiona associated with the rejection of a pig-to-human liver xenograft. Transplant Proc 26:1074–1075.PubMedGoogle Scholar
  19. 19.
    Makowka L. 1995. The use of a pig liver xenograft for the temporary support of a patient with fulminanat hepatic failure. Transplantation 59:1654–1659.CrossRefGoogle Scholar
  20. 20.
    Abouna GM. 1997. Extracorporeal xenogenic liver perfusion for the treatment of hepatic failure. In: Xenotransplantation: The Transplantation of Organs and Tissues Between Species. Ed. DKC Cooper, E Kemp, JL Piatt, DJG White, 785–793. New York: Springer.Google Scholar
  21. 21.
    State of the art report on Xenotransplantation (2000)—Clinical Activities. 2000. (Online). Council of Europe, Scholar
  22. 22.
    Korbutt GS, Aspeslet L, Ao Z, Warnock GL, Ezekowitz J, Koshal A, Rajotte RV, Yatscoff RW. 1996. Porcine islet cell antigens are recognized by xenoreactive natural human antibodies of both IgG and IgM subtypes. Transplant Proc 28:837–838.PubMedGoogle Scholar
  23. 23.
    Rayat GR, Rajotte RV, Elliott JF, Korbutt GS. 1998. Gal alpha(1,3)Gal expression on neonatal porcine islet cells and susceptibility to human antibody/complement lysis. Transplant Proc 30:325.PubMedCrossRefGoogle Scholar
  24. 24.
    Korbutt GS, Ao Z, Flashner M, Rajotte RV. 1997. Neonatal porcine islets as a possible source of tissue for humans and microencapsulation improves the metabolic response of islet graft posttransplantation. Ann NY Acad Sci 831:294–303.PubMedCrossRefGoogle Scholar
  25. 25.
    Rayat GR, Rajotte RV, Ao Z, Korbutt GS. 2000. Microencapsulation of neonatal porcine islets: protection from human antibody/complement-mediated cytolysis in vitro and long-term reversal of diabetes in nude mice. Transplantation 69:1084–1090.PubMedCrossRefGoogle Scholar
  26. 26.
    Piatt JL. 2001. A primer on xenotransplantation. In: Xenotransplantation. Ed. JL Piatt, 3–28. Washington: ASM Press.Google Scholar
  27. 27.
    Thomas F. 1997. Isolated pancreatic islet xenografting. In: Xenotransplantation: The Transplantation of Organs and Tissues Between Species. Ed. DKC Cooper, E Kemp, JL Piatt, DJG White, 545–565. New York: Springer.Google Scholar
  28. 28.
    Rabinovitch A, Suarez-Pinzon W, Strynadka K, Ju Q, Edelstein D, Brownlee M, Korbutt GS, Rajotte RV. 1999. Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects beta-cells from cytokine-induced destruction. Diabetes 48:1223–1229.PubMedCrossRefGoogle Scholar
  29. 29.
    Groth CG, Korsgren O, Tibell A, Reinholt F, Wennberg L, Satake M, Moller E, Rydberg L, Samuelsson B, Andersson A, Hellerstrom C. 1997. Clinical islet xenotransplantation. In: Xenotransplantation: The Transplantation of Organs and Tissues Between Species. Ed. DKC Cooper, E Kemp, JL Piatt, DJG White, 812–821. New York: Springer.Google Scholar
  30. 30.
    Hammer C. 1997. Evolutionary obstacles to xenotransplantation. In: Xenotransplantation: The Transplantation of Organs and Tissues Between Species. Ed. DKC Cooper. E Kemp, JL Piatt, DJG White, 716–736. New York: Springer.Google Scholar
  31. 31.
    Van der Riet FS, Human PA, Cooper DKC, Reichart B, Fincham JE, Kalter SS, Kanki PJ, Essex M, Madden DL, Lai-Tung MT. 1987. Virological implications of the use of primates in xenotransplantation. Transplant Proc 19:4068–4069.PubMedGoogle Scholar
  32. 32.
    Chapman LE, Folks TM, Salomon DR, Patterson TE, Eggerman TE, Noguchi PD. 1995. Xenotransplantation and xenogenic infection. N Engl J Med 333:1498-1501.PubMedCrossRefGoogle Scholar
  33. 33.
    Luo Y, Taniguchi S, Kobayashi T, Niekrasz M, Cooper DKC. 1995. Screening of baboon potential liver donors for humans. Xenotransplantation 2:244–252.CrossRefGoogle Scholar
  34. 34.
    Sachs DH. 1994. The pig as a potential xenograft donor. Vet Immunol Immunopathol 43:185–191.PubMedCrossRefGoogle Scholar
  35. 35.
    Sachs DH. 1994. The pig as a xenograft donor. Pathol Biol (Paris) 42:217–219.Google Scholar
  36. 36.
    Calne RY. 1970. Organ Transplantation Between Widely Disparate Species. Transplant Proc 2:553.Google Scholar
  37. 37.
    Piatt JL. 1997. Hyperacute xenograft rejection. In: Xenotransplantation: The Transplantation of Organs and Tissues Between Species. Ed. DKC Cooper, E Kemp, JL Piatt, DJG White, 8–17. New York: Springer.Google Scholar
  38. 38.
    Schilling A, Land W, Pratschke E, et al. 1976. Dominant role of complement in the hyperacute xenograft rejection reaction. Surgery; Gynecology & Obstetrics 142:29–32.Google Scholar
  39. 39.
    Auchincloss H. 1988. Xenogenic transplantation: a review. Transplantation 46:1–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Platt JL, Vercellotti GM, Dalmasso AP. 1990. Transplantation of discordant xenografts: a review of progress. Immunol Today 11:450–456.PubMedCrossRefGoogle Scholar
  41. 41.
    Holtzknecht ZE, Piatt JL. 1995. Identification of porcine endothelial cell membrane antigens recognized by human xenoreactive natural antibodies. Journal of Immunology 154:4565–4575.Google Scholar
  42. 42.
    Good AH, Cooper DK, Malcolm AJ, Ippolito RM, Koren E, Neethling FA, Ye Y, Zuhdi N, Lamontagne LR. 1992. Identification of carbohydrate structures that bind human antiporcine antibodies: implications for discordant xenografting in humans. Transplant Proc 24:559–562.PubMedGoogle Scholar
  43. 43.
    Sandrin MS, Vaughan HA, Dabkowski PL, McKenzie IF. 1993. Anti-pig IgM antibodies in human serum react predominantly with Gal(alpha 1–3)Gal epitopes. Proc Natl Acad Sci USA 90: 11391–11395.PubMedCrossRefGoogle Scholar
  44. 44.
    Galili U. 1993. Interaction of the natural anti-Gal antibody with alpha-galactosyl epitopes: a major obstacle for xenotransplantation in humans. Immunol Today 14:480–482.PubMedCrossRefGoogle Scholar
  45. 45.
    Sandrin MS, McKenzie IF. 1994. Gal alpha (1,3)Gal, the major xenoantigen(s) recognised in pigs by human natural antibodies. Immunol Rev 141:169–190.PubMedCrossRefGoogle Scholar
  46. 46.
    Collins BH, Cotterell AH, McCurry KR, Alvarado CG, Magee JC, Parker W, Piatt JL. 1995. Cardiac xenografts between primate species provide evidence for the importance of the alpha-galactosyl determinant in hyperacute rejection. J Immunol 154:5500-5510.PubMedGoogle Scholar
  47. 47.
    Lin SS, Kooyman DL, Daniels LJ, Daggett CW, Parker W, Lawson JH, Hoopes CW, Gullotto C, Li L, Birch P, Davis RD, Diamond LE, Logan JS, Piatt JL. 1997. The role of natural anti-Gal alpha 1–3Gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants. Transpl Immunol 5:212–218.PubMedCrossRefGoogle Scholar
  48. 48.
    Cooper DK, Good AH, Koren E, Oriol R, Malcolm AJ, Ippolito RM, Neethling FA, Ye Y, Romano E, Zuhdi N. 1993. Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. Transpl Immunol 1: 198–205.PubMedCrossRefGoogle Scholar
  49. 49.
    Cooper DK, Koren E, Oriol R. 1994. Oligosaccharides and discordant xenotransplantation. Immunol Rev 141:31–58.PubMedCrossRefGoogle Scholar
  50. 50.
    Galili U, Korkesh A, Kahane I, Rachmilewitz EA. 1983. Demonstration of a natural antigalactosyl IgG antibody on thalassemic red blood cells. Blood 61:1258–1264.PubMedGoogle Scholar
  51. 51.
    Galili U, Clark MR, Shohet SB. 1986. Excessive binding of natural anti-alpha-galactosyl immuno-globin G to sickle erythrocytes may contribute to extravascular cell destruction. J Clin Invest 77: 27–33.PubMedCrossRefGoogle Scholar
  52. 52.
    Galili U, Kobrin E, Macher BA, Shohet SB. 1989. Anti-Gal and human red cell aging. Prog Clin Biol Res 319:225–241.PubMedGoogle Scholar
  53. 53.
    Galili U, Flechner I, Rachmilewitz EA. 1985. A naturally occurring anti-alpha-galactosyl IgG recognizing senescent human red cells. Prog Clin Biol Res 195:263–278.PubMedGoogle Scholar
  54. 54.
    Galili U. 1988. The natural anti-Gal antibody, the B-like antigen, and human red cell aging. Blood Cells 14:205–228.PubMedGoogle Scholar
  55. 55.
    Galili U, Anaraki F, Thall A, Hill-Black C, Radic M. 1993. One percent of human circulating B lymphocytes are capable of producing the natural anti-Gal antibody. Blood 82:2485–2493.PubMedGoogle Scholar
  56. 56.
    Galili U, Shohet SB, Kobrin E, Stults CL, Macher BA. 1988. Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. J Biol Chem 263:17755–17762.PubMedGoogle Scholar
  57. 57.
    Galili U, Swanson K. 1991. Gene sequences suggest inactivation of alpha-1,3-galactosyltransferase in catarrhines after the divergence of apes from monkeys. Proc Natl Acad Sci USA 88:7401–7404.PubMedCrossRefGoogle Scholar
  58. 58.
    Galili U. 1993. Evolution and pathophysiology of the human natural anti-alpha-galactosyl IgG (anti-Gal) antibody. Springer Semin Immunopathol 15:155–171.PubMedCrossRefGoogle Scholar
  59. 59.
    Galili U, Clark MR, Shohet SB, Buehler J, Macher BA. 1987. Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1-3 Gal epitope in primates. Proc Natl Acad Sci USA 84:1369–1373.PubMedCrossRefGoogle Scholar
  60. 60.
    Galili U. 1999. Evolution of alpha 1,3galactosyltransferase and of the alpha-Gal epitope. Subcell Biochem 32:1–23.PubMedGoogle Scholar
  61. 61.
    Wang L, Anaraki F, Henion TR, Galili U. 1995. Variations in activity of the human natural anti-Gal antibody in young and elderly populations. J Gerontol A Biol Sci Med Sci 50:M227–M233.PubMedCrossRefGoogle Scholar
  62. 62.
    Koren E, Neethling FA, Ye Y, Niekrasz M, Baker J, Martin M, Zuhdi N, Cooper DK. 1992. Heterogeneity of preformed human antipig xenogeneic antibodies. Transplant Proc 24:598–601.PubMedGoogle Scholar
  63. 63.
    Avila JL, Rojas M, Galili U. 1989. Immunogenic Gal alpha 1–3 Gal carbohydrate epitopes are present on pathogenic American Trypanosoma and Leishmania. J Immunol 142:2828–2834.PubMedGoogle Scholar
  64. 64.
    Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffiss JM. 1988. Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun 56: 1730–1737.PubMedGoogle Scholar
  65. 65.
    Vaughan HA, Loveland BE, Sandrin MS. 1994. Gal alpha(1,3)Gal is the major xenoepitope expressed on pig endothelial cells recognized by naturally occurring cytotoxic human antibodies. Transplantation 58:879–882.PubMedCrossRefGoogle Scholar
  66. 66.
    Galili U. 1989. Abnormal expression of alpha-galactosyl epitopes in man. A trigger for autoimmune processes? Lancet 2:358–361.PubMedCrossRefGoogle Scholar
  67. 67.
    Galili U. 1999. Graves’ disease as a model for anti-Gal involvement in autoimmune diseases. Subcell Biochem 32:339–360.PubMedGoogle Scholar
  68. 68.
    Galili U, Macher BA. 1989. Interaction between anti-Gal and human tumor cells: a natural defense mechanism? J Natl Cancer Inst 81:178–179.PubMedCrossRefGoogle Scholar
  69. 69.
    Galili U, Flechner I, Knyszynski A, Danon D, Rachmilewitz EA. 1986. The natural anti-alpha-galactosyl IgG on human normal senescent red blood cells. Br J Haematol 62:317–324.PubMedCrossRefGoogle Scholar
  70. 70.
    Lane PA, Galili U, Iarocci TA, Shew RL, Mentzer WC. 1988. Cellular dehydration and immunoglobulin binding in senescent neonatal erythrocytes. Pediatr Res 23:288–292.PubMedCrossRefGoogle Scholar
  71. 71.
    McMorrow IM, Comrack CA, Sachs DH, DerSimonian H. 1997. Heterogeneity of human anti-pig natural antibodies cross-reactive with the Gal(alpha1,3)Galactose epitope. Transplantation 64: 501–510.PubMedCrossRefGoogle Scholar
  72. 72.
    McKenzie IF, Xing PX, Vaughan HA, Prenzoska J, Dabkowski PL, Sandrin MS. 1994. Distribution of the major xenoantigen (gal (alpha 1–3)gal) for pig to human xenografts. Transpl Immunol 2: 81–86.PubMedCrossRefGoogle Scholar
  73. 73.
    Kobayashi T, Cooper DKC. 1999. Anti-Gal, α-Gal epitopes and xenotransplantation. Subcell Biochem 32:229–259.PubMedGoogle Scholar
  74. 74.
    Blakely ML. 1994. Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection. Transplantation 58:1059–1066.PubMedGoogle Scholar
  75. 75.
    Piatt JL. 1994. A perspective on xenograft rejection and accommodation. Immunol Rev 141:127–149.CrossRefGoogle Scholar
  76. 76.
    Bach FH. 1994. Xenotransplantation: problems posed by endothelial cell activation. Transplant Proc 26:1020–1030.Google Scholar
  77. 77.
    Bach FH, Stuhlmeier KM, Vanhove B, Van der Werf WJ, Blakely ML, de Martin R, Hancock WW, Winkler H. 1994. Endothelial cells in xenotransplantation: Do they accomodate? Transplant Proc 26:1167–1169.PubMedGoogle Scholar
  78. 78.
    Malyguine AM, Saadi S, Piatt JL. 1996. Human natural killer cells induce morphologic changes in porcine endothelial cell monolayers. Transplantation 61:161–164.PubMedCrossRefGoogle Scholar
  79. 79.
    Hancock WW, Miyatake T, Koyamada N, Kut JP, Soares M, Russell ME, Bach FH, Sayegh MH. 1997. Effects of leflunomide and deoxyspergualin in the guinea pig→rat cardiac model of delayed xenograft rejection: suppression of B cell and C-C chemokine responses but not induction of macrophage lectin. Transplantation 64:696–704.PubMedCrossRefGoogle Scholar
  80. 80.
    Goodman DJ, Von Albertini M, Wilson A, Millan MT, Bach FH. 1996. Direct activation of porcine endothelial cells by human natural killer cells. Transplantation 61:763–771.PubMedCrossRefGoogle Scholar
  81. 81.
    Bach FH, Robson SC, Winkler H, Ferran C, Stuhlmeier KM, Wnghton CJ, Hancock WW. 1995. Barriers to xenotransplantation. Nat Med 1:869–873.PubMedCrossRefGoogle Scholar
  82. 82.
    Palmetshofer A, Galili U, Dalmasso AP, Robson SC, Bach FH. 1998. Alpha-galactosyl epitope-mediated activation of porcine aortic endothelial cells: type I activation. Transplantation 65:844–853.PubMedCrossRefGoogle Scholar
  83. 83.
    Palmetshofer A, Galili U, Dalmasso AP, Robson SC, Bach FH. 1998. Alpha-galactosyl epitopemediated activation of porcine aortic endothelial cells: type II activation. Transplantation 65: 971–978.PubMedCrossRefGoogle Scholar
  84. 84.
    Mantovani AF, Bussolino AF, Dejana E. 1992. Cytokine regulation of endothelial cell function. FASEB J 6:2591–2599.PubMedGoogle Scholar
  85. 85.
    Piatt JL, Fischel RJ, Matas AJ, Reif SA, Bolman RM, Bach FH. 1991. Immunopathology of hyperacute xenograft rejection in a swine-to-primate model. Transplantation 52:214–220.CrossRefGoogle Scholar
  86. 86.
    Lexer G, Cooper DK, Rose AG, Wicomb WN, Rees J, Keraan M, Du TE. 1986. Hyperacute rejection in a discordant (pig to baboon) cardiac xenograft model. J Heart Transplant 5:411–418.PubMedGoogle Scholar
  87. 87.
    Dalmasso AP. 1991. Inhibition of complement-mediated endothelial cell cytotoxicity by decay accelerating factor: potential for prevention of xenograft hyperacute rejection. Transplantation 52: 530–533.PubMedCrossRefGoogle Scholar
  88. 88.
    Rose AG, Cooper DK, Human PA, Reichenspurner H, Reichart B. 1991. Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts. J Heart Lung Transplant 10:223–234.PubMedGoogle Scholar
  89. 89.
    Rose AG, Cooper DK. 1996. A histopathologic grading system of hyperacute (humoral, antibody-mediated) cardiac xenograft and allograft rejection. J Heart Lung Transplant 15:804–817.PubMedGoogle Scholar
  90. 90.
    Ye Y, Neethling FA, Niekrasz M, Koren E, Richards SV, Martin M, Kosanke S, Onol R, Cooper DK. 1994. Evidence that intravenously administered alpha-galactosyl carbohydrates reduce baboon serum cytotoxicity to pig kidney cells (PK15) and transplanted pig hearts. Transplantation 58: 330–337.PubMedGoogle Scholar
  91. 91.
    Ye Y, Neethling FA, Niekrasz M, Richards SV, Koren G, Merhav H, Kosanke S, Oriol R, Cooper DK. 1994. Intravenous administration of alpha-galactosyl carbohydrates reduces in vivo baboon serum cytotoxicity to pig kidney cells and transplanted pig hearts. Transplant Proc 26: 1399.PubMedGoogle Scholar
  92. 92.
    Neethling FA, Koren E, Ye Y, Richards SV, Kujundzic M, Oriol R, Cooper DK. 1994. Protection of pig kidney (PK15) cells from the cytotoxic effect of anti-pig antibodies by alpha-galactosyl oligosaccharides. Transplantation 57:959–963.PubMedCrossRefGoogle Scholar
  93. 93.
    Rieben R. 1995. Detection immunoadsorption and inhibition of cytotoxic activity of anti-α-gal antibodies using newly developed substances with synthetic Gal α 1,3 Gal disaccharide epitopes. Xenotransplantation 2:98–106.CrossRefGoogle Scholar
  94. 94.
    Cairns T, Lee J, Goldberg L, Cook T, Simpson P, Spackman D, Palmer A, Taube D. 1995. Inhibition of the pig to human xenograft reaction, using soluble Gal alpha 1–3Gal and Gal alpha 1–3Gal beta 1–4GlcNAc. Transplantation 60:1202–1207.PubMedGoogle Scholar
  95. 95.
    Azimzadeh A, Watier H, Meyer C, Guillaumin JM, Beller JP, Kieny R, Zibolt P, Boudjema K, Jaeck D, Cinqualbre J, Wolf P. 1997. Rebound in complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxic activity in primate serum after pig liver perfusion. Transplantation 29:2385–2386.Google Scholar
  96. 96.
    Cooper DK. 1996. Experimental progress and clinical perspectives in xenotransplantation. Transplant Proc 28:1153.PubMedGoogle Scholar
  97. 97.
    Aspeslet LJ, Chackowsky P, Sekhon H, Malcolm AJ, Mosleh Z, Koshal A, Yatscoff RW. 1996. Identification of porcine membrane antigens involved in the cytotoxic response mediated by human xenoreactive antibodies. Xenotransplantation 3:1–10.CrossRefGoogle Scholar
  98. 98.
    Pascher A, Poehlein C, Stangl M, Hoebel G, Thiery J, Mueller-Derlich J, Hammer C. 1997. Application of immunoapheresis for delaying hyperacute rejection during isolated xenogeneic pig liver perfusion. Transplantation 63:867–875.PubMedCrossRefGoogle Scholar
  99. 99.
    Leventhal J, Fryer JP, Witson JC, Derlich JM, Remiszewski J, Dalmasse AP, Matas AJ, Bolman RM. 1995. Removal of baboon and human anti-porcine IgG and IgM natural antibodies by immunoadsorption: Results of in vitro and in vivo studies. Transplantation 59:294–300.PubMedGoogle Scholar
  100. 100.
    Taniguchi S, Neethling FA, Korchagina EY, Bovin N, Ye Y, Kobayashi T, Niekrasz M, Li S, Koren E, Oriol R, Cooper DK. 1996. In vivo immunoadsorption of antipig antibodies in baboons using a specific Gal(alpha)1–3Gal column. Transplantation 62:1379–1384.PubMedCrossRefGoogle Scholar
  101. 101.
    Manji RA, Manji JS, Rajotte RV, Afrouzian M, Yatscoff RW, Koshal A. 2000. Specific α-gal antibody removal and human ABO blood group in human-porcine cardiac xenograft survival. Can J Cardiol 16:211F.Google Scholar
  102. 102.
    Ryan US. 1995. Complement inhibitory therapeutics and xenotransplantation. Nat Med 1995: 967–968.CrossRefGoogle Scholar
  103. 103.
    Kobayashi T, Taniguchi S, Neethling FA, Rose AG, Hancock WW, Ye Y, Niekrasz M, Kosanke S, Wright LJ, White DJ, Cooper DK. 1997. Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy. Transplantation 64:1255–1261.PubMedCrossRefGoogle Scholar
  104. 104.
    Pruitt SK, Kirk AD, Bollinger RR, Marsh HC, Collins BH, Levin JL, Mault JR, Heinle JS, Ibrahim S, Rudolph AR. 1994. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation 57:363–370.PubMedCrossRefGoogle Scholar
  105. 105.
    Cozzi E, White DJG. 1995. The generation of transgenic pigs as potential organ donors for humans. Nat Med 1:964–966.PubMedCrossRefGoogle Scholar
  106. 106.
    van Denderen BJW, Pearse MJ, Katerelos M, Nottle MB, Du ZT, Aminian A, Adam WR, Shenoy-Scaria A, Lublin D, Shinkel TA, d’Apice AJ. 1996. Expression of a functional human decay-accelerating factor (CD55) in transgenic mice protects against human complement-mediated attack. Transplantation 61:582–588.PubMedCrossRefGoogle Scholar
  107. 107.
    Fodor WL, Williams BL, Matis LA, Madn JA, Rollins SA, Knight JW, Velander W, Squinto SP. 1994. Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogenic hyperacute rejection. Proc Natl Acad Sci USA 91:11153–11157.PubMedCrossRefGoogle Scholar
  108. 108.
    Chong A, Blinder L, Ma L, Yin D, Shen J, Williams JW, Byrne G, Schwarz A, Diamond LS, Logan JE. 2000. Anti-galactose-alpha(1,3) galactose antibody production in alpha1,3-galactosyltransferase gene knockout mice after xeno and allo transplantation. Transpl Immunol 8:129–137.PubMedCrossRefGoogle Scholar
  109. 109.
    Cowan PJ, Chen CG, Shinkel TA, Fisicaro N, Salvaris E, Aminian A, Romanella M, Pearse MJ, d’Apice AJ. 1998. Knock out of alpha 1,3-galactosyltransferase or expression of alpha1,2-fucosyltransferase further protects CD55- and CD59-expressing mouse hearts in an ex vivo model of xenograft rejection. Transplantation 65:1599–1604.PubMedCrossRefGoogle Scholar
  110. 110.
    Kaiser J. 2002. Making pigs more like people. ScienceNOW 103:1–3.Google Scholar
  111. 111.
    Costa C, Zhao L, Burton WV, Bondioli KR, Williams BL, Hoagland TA, Ditullio PA, Ebert KM, Fodor WL. 1999. Expression of the human alpha 1,2-fucosyltransferase in transgenic pigs modifies the cell surface carbohydrate phenotype and confers resistance to human serum-mediated cytolysis. FASEB J 13:1762–1773.PubMedGoogle Scholar
  112. 112.
    Cheng Q, Cant CA, Moll T, Hofer-Warbinek R, Wagner E, Birnstiel ML, Bach FH, de Martin R. 1994. NFκB subunit specific regulation of the IκBα promoter. J Biol Chem 269:13551.PubMedGoogle Scholar
  113. 113.
    Winkler H. 1995. Genetic engineering of endothelial cells. Xenotransplantation 2:197–200.CrossRefGoogle Scholar
  114. 114.
    Bach F, Robson SC, Ferran C, Millan MT, Anrather J, Kopp C, Lesnikoski B, Goodman DJ, Hancock WW, Wrighton CJ. 1995. Xenotransplantation: Endothelial cell activation and beyond. Transplant Proc 27:77.PubMedGoogle Scholar
  115. 115.
    Zehr KJ, Herskowitz A, Lee PC, Kumar P, Gillinov AM, Baumgartner WA. 1994. Neutrophil adhesion and complement inhibition prolongs survival of cardiac xenografts in discordant species. Transplantation 57:900–906.PubMedCrossRefGoogle Scholar
  116. 116.
    Coughlan AF, Berndt MC, Dunlop LC, Hancock WW. 1993. In vivo studies of P-selectin and platelet-activating factor during endotoxemia, accelerated graft rejection and discordant xenograft rejection. Transplant Proc 25:2930.PubMedGoogle Scholar
  117. 117.
    Lesnikoski BA, Candinas D, Hancock WW, Otsu I, Siegel J, Bach FH, Robson SC. 1996. Inhibition of platelet GPIIbllla prolongs survival of discordant cardiac xenografts. Transplant Proc 28:703.PubMedGoogle Scholar
  118. 118.
    Robson SC, Young VK, Cook NS, Metternich R, Kasper-Konig W, Lesnikoski BA, Pierson RN, Hancock WW, Candinas D, White DJ, Bach FH. 1996. Thrombin inhibition in an ex vivo model of porcine heart xenograft hyperacute rejection. Transplantation 61:862–868.PubMedCrossRefGoogle Scholar
  119. 119.
    Mark W. 1997. Xenograft accomodation is accompanied by intragraft Th2 cytokines and vascular expression of protective genes. Xenotransplantation 4:154–160.CrossRefGoogle Scholar
  120. 120.
    Lin SS, Weidner BC, Byrne GW, Diamond LE, Lawson JH, Hoopes CW Daniels LJ, Daggett CW, Parker W, Harland RC, Davis RD, Bollinger RR, Logan JS, Piatt JL. 1998. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. J Clin Invest 101:1745–1756.PubMedCrossRefGoogle Scholar
  121. 121.
    Candinas D, Bach FH, Hancock WW. 1996. Delayed xenograft rejection in complement-depleted T-cell-deficient rat recipients of guinea pig cardiac grafts. Transplant Proc 28:678.PubMedGoogle Scholar
  122. 122.
    McCurry KR, Parker W, Cotterell AH, Weidner BC, Lin SS, Daniels LJ, Holzknecht ZE, Byrne GW, Diamond LE, Logan JS, Piatt JL. 1997. Humoral responses to pig-to-baboon cardiac transplantation: implications for the pathogenesis and treatment of acute vascular rejection and for accommodation. Hum Immunol 58:91–105.PubMedCrossRefGoogle Scholar
  123. 123.
    Lin SS, Hanaway MJ, Gonzalez-Stavvinski GV, Lau CL, Parker W. Davis RD, Byrne GW, Diamond LE, Logan JS, Piatt JL. 2000. The role of anti-Galalpha1-3Gal antibodies in acute vascular rejection and accommodation of xenografts. Transplantation 70:1667–1674.PubMedCrossRefGoogle Scholar
  124. 124.
    Lin SS, Piatt JL. 1998. Genetic therapies for xenotransplantation. J Am Coll Surg 186:388–396.PubMedCrossRefGoogle Scholar
  125. 125.
    Kirk AD. 1999. Transplantation tolerance: a look at the nonhuman primate literature in the light of modern tolerance theories. Crit Rev Immunol 19:349–388.PubMedCrossRefGoogle Scholar
  126. 126.
    Sachs DH. 1998. Transplantation tolerance. Transplant Proc 30:1627–1629.PubMedCrossRefGoogle Scholar
  127. 127.
    Yang YG, deGoma E, Ohdan H, Bracy JL, Xu Y, Iacomini J, Thall AD, Sykes M. 1998. Tolerization of anti-Galalphal-3Gal natural antibody-forming B cells by induction of mixed chimensm. J Exp Med 187:1335–1342.PubMedCrossRefGoogle Scholar
  128. 128.
    Bartholomew AM, Powelson J, Sachs DH, Bailin M, Boskovic S, Colvin R, Hong HZ, Johnson M, Kimikawa M, LeGuern A, Meehan S, Sablinski T, Wee SL, Cosimi AB. 1999. Tolerance in a concordant nonhuman primate model. Transplantation 68:1708–1716.PubMedCrossRefGoogle Scholar
  129. 129.
    Alexandre GP, Squifflet JP, De Bruyere M, Latinne D, Reding R, Gianello P, Carlier M, Pirson Y. 1987. Present experience in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc 19:4538.PubMedGoogle Scholar
  130. 130.
    Soares MP, Lin Y, Anrather J, Csizmadia E, Takigami K, Sato K, Grey ST, Colvin KB, Choi AM, Poss KD, Bach FH. 1998. Expression of heme oxygenase-1 can determine cardiac xenograft survival. Nat Med 4:1073–1077.PubMedCrossRefGoogle Scholar
  131. 131.
    Buhler L, Sachs DH, Alwayn IPJ, Cooper DKC. 2001. Therapeutic Strategies for Xenotransplantation. In: Xenotransplantation. Ed. JL Piatt, 117–135. Washington: ASM Press.Google Scholar
  132. 132.
    Hammer C. 1998. Physiological obstacles after xenotransplantation. Ann N Y Acad Sci 862: 19–27.PubMedCrossRefGoogle Scholar
  133. 133.
    Hammer C. 1994. Fundamental problems of xenotransplantation. Pathol Biol (Paris) 42:203–207.Google Scholar
  134. 134.
    Hammer C. 1991. Xenotransplantation: perspectives and limits. Blood Purif 19:322–328.CrossRefGoogle Scholar
  135. 135.
    Buhler L, Yamada K, Alwayn I, Kitamura H, Basker M, Barth RN, Appel J, Awwad M, Thall A, White-Scharf ME, Sachs DH, Cooper DK. 2001. Miniature swine and hDAF pig kidney transplantation in baboons treated with a nonmyeloablative regimen and CD 154 blockade. Transplant Proc 33:716.PubMedCrossRefGoogle Scholar
  136. 136.
    Zaidi A, Schmoeckel M, Bhatti FN, Waterworth PD, Tolan M, Cozzi E, Chavez G, Langford G, Thiru S, Wallwork J, White D, Friend P. 1998. Life-supporting pig-to-primate renal xenotransplantation using genetically modified donors. Transplantation 65:1584–1590.PubMedCrossRefGoogle Scholar
  137. 137.
    Schmoeckel M, Bhatti FN, Zaidi A, Cozzi E, Waterworth PD, Tolan MJ, Pino-Chavez G, Goddard M, Warner RG, Langford GA, Dunning JJ, Wallwork J, White DJ. 1998. Orthotopic heart transplantation in a transgenic pig-to-primate model. Transplantation 65:1570–1577.PubMedCrossRefGoogle Scholar
  138. 138.
    Daggett CW, Yeatman MF, Lodge AJ, Chen EP, Gullotto C, Frank MM, Piatt JL, Davis RD. 1998. Total respiratory support from swine lungs in primate recipients. J Thorac Cardiovasc Surg. 115: 19–27.PubMedCrossRefGoogle Scholar
  139. 139.
    Chari RS, Collins BH, Magee JC, Kirk AD, Harland RC, McCann RL, Piatt JL, Meyers WC. 1994. Treatment of hepatic failure with ex-vivo pig liver perfusion followed by liver transplantation. N Engl J Med 331:234–237.PubMedCrossRefGoogle Scholar
  140. 140.
    Takeuchi Y, Patience C, Magre S, Weiss RA, Banerjee PT, Le Tissier P, Stoye JP. 1998. Host range and interference studies of three classes of pig endogenous retrovirus. J Virol 72:9986–9991.PubMedGoogle Scholar
  141. 141.
    Patience C, Patton GS, Takeuchi Y, Weiss RA, McClure MO, Rydberg L, Breimer ME. 1998. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet 352:699–701.PubMedCrossRefGoogle Scholar
  142. 142.
    State of the Art Report on Serological Screening Methods for the Most Relevant Microbiological Disease. 2000. (Online). Council of Europe,
  143. 143.
    Qari SH, Magre S, Garcia-Lerma JG, Hussain AI, Takeuchi Y, Patience C, Weiss RA, Heneine W. 2001. Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors. J Virol 75:1048–1053.PubMedCrossRefGoogle Scholar
  144. 144.
    Manji RA, Manji JS, Rajotte RV, Korbutt GS, Koshal A. 2001. Critical factors in survival of a pig-human xenograft. Can J Cardiol 17:243c.Google Scholar
  145. 145.
    Manji RA, Manji JS, Koshal A, Korbutt GS, Rajotte RV. 2001. The ideal human ABO blood group and red blood cells for porcine-to-human cardiac xenotransplantation. Xenotransplantation 8:95.Google Scholar
  146. 146.
    Buchser E, Goddard M, Heyd B, Joseph JM, Favre J, de Tribolt N, Lysaght M, Aebischer P. 1996. Immunoisolated xenogenic chromaffine cells therapy for chronic pain. Anesthesiology 85:1005–1012.PubMedCrossRefGoogle Scholar
  147. 147.
    Zurn AD, Henry H, Schluep M, Aubert V, Winkel L, Eilers B, Bachmann C, Aebischer P. 2000. Evaluation of an intrathecal immune response in amyotrophic lateral sclerosis patients implanted with encapsulated genetically engineered xenogeneic cells. Cell Transplant 9:471–484.PubMedGoogle Scholar
  148. 148.
    Fink JS, Schumacher JM, Ellias SL, Palmer EP, Saint-Hilaire M, Shannon K, Penn R, Starr P, VanHorne C, Kott HS, Dempsey PK, Fischman AJ, Raineri R, Manhart C, Dinsmore J, Isacson O. 2000. Porcine xenografts in Parkinson’s disease and Huntington’s disease patients: preliminary results. Cell Transplant 9:273–278.PubMedGoogle Scholar
  149. 149.
    Groth CG, Korsgren O, Tibell A, Tollemar J, Moller E, Bolinder J, Ostman J, Reinholt FP, Hellerstrom C, Andersson A. 1994. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 344:1402–1404.PubMedCrossRefGoogle Scholar
  150. 150.
    Taylor R. 1996. Baboon graft fails, but patient thrives. Nat Med 2:259.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2004

Authors and Affiliations

  • Rizwan A. Manji
    • 1
    • 2
  • Jacqueline S. Manji
    • 2
  • Ray V. Rajotte
    • 2
  • Arvind Koshal
    • 1
  1. 1.The Division of Cardiac SurgeryDepartment of SurgeryEdmontonCanada
  2. 2.Surgical Medical Research Institute, 1074 Dentistry/Pharmacy CentreUniversity of AlbertaEdmontonCanada

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