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Semin Liver Dis 2000; 20(4): 511-522
DOI: 10.1055/s-2000-13159
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Prospects for Xenotransplantation of the Liver

Akiyoshi Kanazawa1 , Jeffrey L. Platt2
  • Departments of Surgery and Immunology,
  • 1 Mayo Clinic, Rochester, Minnesota and Departments of Surgery and Pediatrics
  • 2, Mayo Clinic, Rochester, Minnesota. Reprint request: Dr. Jeffrey L. Platt, Transplantation Biology, 2-66 Medical Sciences Building, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905. E-mail: platt.jeffrey@mayo.edu
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

A severe shortage of human livers for allotransplantation has sparked interest in the potential use of animals in lieu of humans as a source of livers, that is xenotransplantation. Xenotransplantation might also provide a means by which recurrence of hepatitis might be averted. Among the types of xenografts that might be undertaken are extracorporeal ``xenoperfusion'' or perfusion of devices containing xenogeneic hepatocytes, auxiliary liver transplants, bridge liver transplants, and hepatocyte transplants. The hurdles to xenotransplantation of the liver include the immune response of the recipient against the graft, incompatibility of the graft with complex physiologic and biochemical systems of the recipient, and the possibility of transferring infectious agent from the graft to the recipient. Recent progress in characterizing and overcoming these hurdles has encouraged some optimism regarding the ultimate application of xenotransplantation for the treatment of human disease.

KEYWORD

xenotransplantation - liver - immunology

REFERENCES

  • 1 Harper A M, Rosendale J D, McBride M A, Cherikh W S, Ellison M D. The UNOS OPTN waiting list and donor registry.  Clin Transpl . 1998;  3
    PubMedGoogle Scholar
  • 2 Starzl T E, Fung J, Tzakis A. Baboon-to-human liver transplantation.  Lancet . 1993;  341 65-71
    CrossrefPubMedGoogle Scholar
  • 3 Blau H M, Springer M L. Muscle-mediated gene therapy.  N Engl J Med . 1995;  333 1554-1556
    CrossrefPubMedGoogle Scholar
  • 4 Platt J L. New directions for organ transplantation.  Nature . 1998;  392(suppl) 11-17
    CrossrefPubMedGoogle Scholar
  • 5 Reemtsma K, McCracken B H, Schlegel J U. Renal heterotransplantation in man.  Ann Surg . 1964;  160 384-410
    PubMedGoogle Scholar
  • 6 Allan J S. Xenotransplantation at a crossroads: prevention versus progress.  Nat Med . 1996;  2 18-21
    PubMedGoogle Scholar
  • 7 White D, Wallwork J. Xenografting: probability, possibility, or pipe dream?.  Lancet . 1993;  342 879-880
    CrossrefPubMedGoogle Scholar
  • 8 Platt J L, Logan J S. Use of transgenic animals in xenotransplantation.  Transplantation Reviews . 1996;  10 69-77
    CrossrefPubMedGoogle Scholar
  • 9 Kelly D A, Mayer D. Liver transplantation. In: Kelly DA, ed. Diseases of the Liver and Biliary System in Children Oxford: Blackwell Science 1999: 293-312
    Google Scholar
  • 10 Rosen H, Shackeleton C, Martin P. Indications for and timing of liver transplantation. In: Martin P, Friedman L, eds. The Medical Clinics of North America: Management of Chronic Liver Disease Philidelphia: WB Saunders 1996: 1069-1102
    Google Scholar
  • 11 Starzl T E, Tzakis A, Fung J J. Prospects of clinical xenotransplantation.  Transpl Proc . 1994;  26 1082-1088
    PubMedGoogle Scholar
  • 12 Taniguchi S, Cooper D KC. Clinical xenotransplantation-a brief review of the world experience. In: Cooper DKC, Kemp E, Platt JL, White DJG, eds. Xenotransplantation 2nd ed. Berlin: Springer-Verlag 1997: 776-784
    Google Scholar
  • 13 Starzl T E, Putnam C W, Porter K A. Progress in and deterrents to orthotopic liver transplantation, with special reference to survival, resistance to hyperacute rejection, and biliary duct reconstruction.  Transpl Proc . 1974;  6 129-139
    PubMedGoogle Scholar
  • 14 Giles G R, Boehmig H J, Amemiya H, Halgrimson C G, Starzl T E. Clinical heterotransplantation of the liver.  Transpl Proc . 1970;  2 506-512
    PubMedGoogle Scholar
  • 15 Starzl T E. Liver transplantation.  Gastroenterology . 1997;  112 288-291
    PubMedGoogle Scholar
  • 16 Fung J, Rao A, Phil D, Starzl T. Clinical trials and projected future of liver xenotransplantation.  World J Surg . 1997;  21 956-961
    CrossrefPubMedGoogle Scholar
  • 17 Makowka L, Cramer D V, Hoffman A. The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure.  Transplantation . 1995;  59 1654-1659
    CrossrefPubMedGoogle Scholar
  • 18 Rela M, Muiesan P, Vilca-Melendez H. Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type I.  Ann Surg . 1999;  229 565-569
    CrossrefPubMedGoogle Scholar
  • 19 Wang X, Andersson R. Hepatocyte transplantation: a potential treatment for acute liver failure.  Scand J Gastroenterol . 1995;  30 193-200
    PubMedGoogle Scholar
  • 20 Kobayashi N, Fujiwara T, Westerman K A. Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes.  Science . 2000;  287 1258-1262
    CrossrefPubMedGoogle Scholar
  • 21 Fox I, Chowdhury J, Kaufman S. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation.  N Engl J Med . 1998;  338 1422-1426
    PubMedGoogle Scholar
  • 22 Lake J. Hepatocyte Transplantation.  N Engl J Med . 1998;  338 1463-1465
    CrossrefPubMedGoogle Scholar
  • 23 Gunsalus J R, Brady D A, Coulter S M, Gray B M, Edge A. Reduction of serum cholesterol in watanabe rabbits by xenogeneic hepatocellular transplantation.  Nat Med . 1997;  3 48-53
    CrossrefPubMedGoogle Scholar
  • 24 Hoopes C W, Platt J L. Hepatocyte transplantation: history, immunology, and potential for clinical application.  Biotech Lab International . 1998;  3 11-14
    PubMedGoogle Scholar
  • 25 Edge A SB, Gosse M E, Dinsmore J. Xenogeneic cell therapy: current progress and future developments in porcine cell transplantation.  Cell Transplantation . 1998;  7 525-539
    CrossrefPubMedGoogle Scholar
  • 26 Wakizaka Y, Miki T, Rao A S. Correction of congenital hyperbilirubinemia in homozygous Gunn rats by xenotransplantation of hamster livers.  Xenotransplantation . 1997;  4 262-266
    PubMedGoogle Scholar
  • 27 Abouna G M, Kirkley J R, Hull C J, Ashcroft T, Kerr D NS. Treatment of hepatic coma by extracorporeal pig-liver perfusion.  Lancet . 1969;  1 64-68
    PubMedGoogle Scholar
  • 28 Chari R S, Collins B H, Magee J C. Treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation.  N Engl J Med . 1994;  331 234-237
    CrossrefPubMedGoogle Scholar
  • 29 Abouna G M. Extracorporeal xenogeneic liver perfusion for the treatment of hepatic failure. In: Cooper DKC, Kemp E, Platt JL, White DJG, eds. Xenotransplantation: the Transplantation of Organs and Tissues between Species 2nd ed. Berlin: Springer; 1997
    Google Scholar
  • 30 Watanabe F D, Mullon C J, Hewitt W R. Clinical experience with a bioartifical liver in the treatment of severe liver failure. A phase I clinical trial.  Ann Surg . 1997;  225 484-491
    CrossrefPubMedGoogle Scholar
  • 31 Chen S C, Mullon C, Kahaku E. Treatment of severe liver failure with a bioartificial liver.  Ann NY Acad Sci . 1997;  831 350-360
    PubMedGoogle Scholar
  • 32 Bismuth H, Figueiro J, Samuel D. What should we expect from a bioartificial liver in fulminant hepatic failure?.  Artificial Organs . 1998;  22 26-31
    CrossrefPubMedGoogle Scholar
  • 33 Platt J L. Hyperacute Xenograft Rejection.  Medical Intelligence Unit. Austin, TX: RG Landes; 1995
    Google Scholar
  • 34 Platt J L, Fischel R J, Matas A J. Immunopathology of hyperacute xenograft rejection in a swine-to-primate model.  Transplantation . 1991;  52 214-220
    PubMedGoogle Scholar
  • 35 Galili U, Clark M R, Shohet S B, Buehler J, Macher B A. Evolutionary relationship between the natural anti-Gal antibody and the Galα1-3Gal epitope in primates.  Proc Natl Acad Sci U S A . 1987;  84 1369-1373
    CrossrefPubMedGoogle Scholar
  • 36 Geller R L, Rubinstein P, Platt J L. Variation in expression of porcine xenogeneic antigens.  Transplantation . 1994;  58 272-277
    PubMedGoogle Scholar
  • 37 Calne R Y, Davis D R, Pena J R. Hepatic allografts and xenografts in primates.  Lancet . 1970;  1 103-106
    PubMedGoogle Scholar
  • 38 Collins B H, Chari R S, Magee J C. Mechanisms of injury in porcine livers perfused with blood of humans with fulminant hepatic failure.  Transplantation . 1994;  58 1162-1171
    PubMedGoogle Scholar
  • 39 Knechtle S J, Kolbeck P C, Tsuchimoto S. Hepatic transplantation into sensitized recipients: demonstration of hyperacute rejection.  Transplantation . 1987;  43 8-12
    PubMedGoogle Scholar
  • 40 Merion R M, Colletti L M. Hyperacute rejection in porcine liver transplantation: I. Clinical characteristics, histopathology, and disappearance of donor-specific lymphocytotoxic antibody from serum.  Transplantation . 1990;  49 861-868
    PubMedGoogle Scholar
  • 41 Lin S S, Kooyman D L, Daniels L J. The role of natural anti-Galα1-3Gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants.  Transpl Immunol . 1997;  5 212-218
    CrossrefPubMedGoogle Scholar
  • 42 Leventhal J R, Dalmasso A P, Cromwell J W. Prolongation of cardiac xenograft survival by depletion of complement.  Transplantation . 1993;  55 857-866
    PubMedGoogle Scholar
  • 43 Pruitt S K, Kirk A D, Bollinger R R. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts.  Transplantation . 1994;  57 363-370
    PubMedGoogle Scholar
  • 44 Magee J C, Collins B H, Harland R C. Immunoglobulin prevents complement mediated hyperacute rejection in swine-to-primate xenotransplantation.  J Clin Invest . 1995;  96 2404-2412
    PubMedGoogle Scholar
  • 45 Platt J L, Vercellotti G M, Dalmasso A P. Transplantation of discordant xenografts: a review of progress.  Immunology Today . 1990;  11 450-456
    CrossrefPubMedGoogle Scholar
  • 46 Logan J S, Martin M J. Transgenic swine as a recombinant production system for human hemoglobin.  Methods in Enzymology . 1994;  231 435-445
    PubMedGoogle Scholar
  • 47 McCurry K R, Kooyman D L, Alvarado C G. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury.  Nat Med . 1995;  1 423-427
    PubMedGoogle Scholar
  • 48 Byrne G W, McCurry K R, Martin M J. Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage.  Transplantation . 1997;  63 149-155
    PubMedGoogle Scholar
  • 49 Cozzi E, Yannoutsos N, Langford G A, Pino-Chavez G, Wallwork J, White D JG. Effect of transgenic expression of human decay-accelerating factor on the inhibition of hyperacute rejection of pig organs. In: Cooper DKC, Kemp E, Platt JL, White DJG, eds. Xenotransplantation: the Transplantation of Organs and Tissues between Species 2nd ed. Berlin: Springer 1997: 665-682
    Google Scholar
  • 50 Dalmasso A P, Vercellotti G M, Platt J L, Bach F H. Inhibition of complement-mediated endothelial cell cytotoxicity by decay accelerating factor: potential for prevention of xenograft hyperacute rejection.  Transplantation . 1991;  52 530-533
    CrossrefPubMedGoogle Scholar
  • 51 Sandrin M S, Fodor W L, Mouhtouris E. Enzymatic remodelling of the carbohydrate surface of a xenogeneic cell substantially reduces human antibody binding and complement-mediated cytolysis.  Nat Med . 1995;  1 1261-1267
    PubMedGoogle Scholar
  • 52 Thall A D, Mal¿ P, Lowe J B. Oocyte Gala1,3Gal epitopes implicated in sperm adhesion to the zona pellucida glycoprotein ZP3 are not required for fertilization in the mouse.  J Biol Chem . 1995;  270 21437-21440
    CrossrefPubMedGoogle Scholar
  • 53 Leventhal J R, Matas A J, Sun L H. The immunopathology of cardiac xenograft rejection in the guinea pig-to-rat model.  Transplantation . 1993;  56 1-8
    PubMedGoogle Scholar
  • 54 Porter K A. Renal Transplantation. In: Heptinstall RH, ed. Pathology of the Kidney, Vol III. 4th ed. Boston, MA: Little, Brown 1992: 1799-1933
    Google Scholar
  • 55 Gugenheim J, Samuel D, Reynes M, Bismuth H. Liver transplantation across ABO blood group barriers.  Lancet . 1990;  336 519-523
    CrossrefPubMedGoogle Scholar
  • 56 Platt J L, Lin S S, McGregor C GA. Acute vascular rejection.  Xenotransplantation . 1998;  5 169-175
    PubMedGoogle Scholar
  • 57 Bach F H, Winkler H, Ferran C, Hancock W W, Robson S C. Delayed xenograft rejection.  Immunology Today . 1996;  17 379-384
    CrossrefPubMedGoogle Scholar
  • 58 Lawson J H, Platt J L. Molecular barriers to xenotransplantation.  Transplantation . 1996;  62 303-310
    PubMedGoogle Scholar
  • 59 Lin S S, Weidner B C, Byrne G W. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.  J Clin Invest . 1998;  101 1745-1756
    CrossrefPubMedGoogle Scholar
  • 60 Chopek M W, Simmons R L, Platt J L. ABO-incompatible renal transplantation: initial immunopathologic evaluation.  Transpl Proc . 1987;  19 4553-4557
    PubMedGoogle Scholar
  • 61 Bannett A D, McAlack R F, Morris M, Chopek M, Platt J L. ABO incompatible renal transplantation: a qualitative analysis of native endothelial tissue ABO antigens after transplant.  Transpl Proc. 1989;  21 783-785
    PubMedGoogle Scholar
  • 62 Parker W, Saadi S, Lin S S, Holzknecht Z E, Bustos M, Platt J L. Transplantation of discordant xenografts: a challenge revisited.  Immunology Today . 1996;  17 373-378
    CrossrefPubMedGoogle Scholar
  • 63 Bach F H, Hancock W W, Ferran C. Protective genes expressed in endothelial cells: a regulatory response to injury.  Immunology Today . 1997;  18 483-486
    CrossrefPubMedGoogle Scholar
  • 64 Sachs D H, Sablinski T. Tolerance across discordant xenogeneic barriers.  Xenotransplantation . 1995;  2 234-239
    PubMedGoogle Scholar
  • 65 Ildstad S T, Vacchio M S, Markus P M, Hronakes M L, Wren S M, Hodes R J. Cross-species transplantation tolerance: rat bone marrow-derived cells can contribute to the ligand for negative selection of mouse T cell receptor Vb in chimeras tolerant to xenogeneic antigens (mouse + rat → mouse).  J Exper Med . 1992;  175 147-155
    CrossrefPubMedGoogle Scholar
  • 66 Zhao Y, Swenson K, Sergio J J, Arn J S, Sachs D H, Sykes M. Skin graft tolerance across a discordant xenogeneic barrier.  Nat Med . 1996;  2 1211-1216
    PubMedGoogle Scholar
  • 67 Inverardi L, Samaja M, Motterlini R, Mangili F, Bender J R, Pardi R. Early recognition of a discordant xenogeneic organ by human circulating lymphocytes.  J Immunol . 1992;  149 1416-1423
    PubMedGoogle Scholar
  • 68 Starzl T E, Demetris A J, Murase N, Ildstad S, Ricordi C, Trucco M. Cell migration, chimerism, and graft acceptance.  Lancet . 1992;  339 1579-1582
    CrossrefPubMedGoogle Scholar
  • 69 Holzknecht Z E, Coombes S, Blocher B A. Evidence of immunocomplex formation in pulmonary xenografts.  Transpl Proc . 2000;  32 1411
    PubMedGoogle Scholar
  • 70 Lawson J H, Platt J L. Xenotransplantation: prospects for clinical application. In: Owen W, Pereira B, M S, eds. Dialysis and Transplantation: A Companion to Brenner and Rector's The Kidney Philadelphia: WB Saunders 2000: 653-660
    Google Scholar
  • 71 Daggett C W, Yeatman M, Lodge A J. Total respiratory support from swine lungs in primate recipients.  J Thorac Cardiovasc Surg . 1998;  115 19-27
    PubMedGoogle Scholar
  • 72 Lawson J H, Daniels L, Platt J L. The evaluation of thrombomodulin activity in porcine to human xenotransplantation.  Transplant Proc . 1997;  29 884-885
    CrossrefPubMedGoogle Scholar
  • 73 Edwards J. Complement activation by xenogeneic red blood cells.  Transplantation . 1981;  31 226-227
    PubMedGoogle Scholar
  • 74 Desille M, Corcos L, L'Helgoualc'h A. Detoxifying activity in pig livers and hepatocytes intended for xenotherapy.  Transplantation . 1999;  68 1437-1443
    PubMedGoogle Scholar
  • 75 Patience C, Takeuchi Y, Weiss R A. Infection of human cells by an endogenous retrovirus of pigs.  Nat Med . 1997;  3 282-286
    CrossrefPubMedGoogle Scholar
  • 76 Patience C, Patton G S, Takeuchi Y. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys.  Lancet . 1998;  352 699-701
    CrossrefPubMedGoogle Scholar
  • 77 Paradis K, Langford G, Long Z. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue.  Science . 1999;  285 1236-1241
    CrossrefPubMedGoogle Scholar
  • 78 Platt J. ``Xenoassistance devices'' for the treatment of hepatic failure: challenges and controversies.  Transpl Proc (in press).
    PubMedGoogle Scholar