Summary
Xenotransplantation offers an alternative source of organs to solve the current critical shortage of donor organs required for patients with end-stage kidney, heart and liver disease. For social, ethical and logistical purposes, pigs appear to be the most appropriate donor animal.
The immunological barriers to xenotransplantation are greater than in allotransplantation because of the presence of preformed natural antibodies in the serum of the recipient. The rapid binding of antibody to donor endothelial cells is followed by complement activation, cell damage and vascular thrombosis. Antirejection therapies aimed at reducing the level of antibody, complement activity and cell-mediated immunity in the recipient may result in a significant increase in complications such as infections and malignancies compared with allotransplantation. Transgenic technology may permit modification of the donor organ, enabling it to evade the rapid antibody- and complement-mediated destruction.
The main strategies to prevent xenotransplant rejection have been to reduce expression of ‘Gal’, the major target epitope for natural antibody, and to inhibit complement activation. Transgenic animals expressing membrane-bound inhibitors of the complement pathway and enzymes that compete for Gal synthesis have been generated. Both approaches provide limited protection, and preliminary experiments in vitro suggest that a combination approach may reduce antibody- and complement-mediated cellular damage.
Similar content being viewed by others
References
d’Apice AJF, Pearse MJ. Xenotransplantation. In: Tilney NL, Strom TB, Paul LC, editors. Transplant biology: cellular and molecular aspects. Piladelphia: Lippincott-Raven Publishers, 1996: 701–16
Reemtsma K, McCracken BH, Schlegel JY, et al. Renal hetero-transplantation in man. Ann Surg 1964; 160: 384–410
Starzl TE, Marchioro TL, Peters GN, et al. Renal hetero-transplantation from baboon to man: experience with 6 cases. Transplantation 1964; 2: 752–76
Bailey LL, Nehlsen-Cannarella SL, Concepcion W, et al. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA 1985; 254: 3321–9
Starzl TE, Fung J, Tzakis A, et al. Baboon-to-human liver transplantation. Lancet 1993; 341: 65–71
Tearle RG, Tange MJ, Zannettino ZL, et al. The α-1,3-galactosyltransferase knockout mouse: implications for xenotransplantation. Transplantation 1996; 61: 13–9
Calne RY. Organ transplantation between widely disparate species. Transplant Proc 1970; 2: 550–6
Galili U. Evolution and pathophysiology of the human natural anti-alpha-galactosyl IgG (Anti-Gal) antibody. Semin Immunopathol 1993; 15: 155–71
Galili U. Interaction of the natural anti-Gal antibody with alpha-galactosyl epitopes: a major obstacle for xenotransplantation in humans. Immunol Today 1993; 14: 480–2
Platt JL, Vercellotti GM, Dalmasso AP, et al. Transplantation of discordant xenografts: a review of progress. Immunol Today 1990; 11: 450–6
Platt JL, Fischel RJ, Matas AJ, et al. Immunopathology of hyperacute xenograft rejection in a swine-to-primate model. Transplantation 1991; 52: 214–20
Platt JL, Dalmasso AP, Vercellotti GM, et al. Endothelial cell proteoglycans in xenotransplantation. Transplant Proc 1990; 22: 1066
Platt JL, Dalmasso AP, Lindman BJ, et al. The role of C5a and antibody in the release of heparan sulfate from endothelial cells. Eur J Immunol 1991; 21: 2887–90
Platt JL, Vercellotti GM, Lindman B, et al. Release of heparan sulfate from endothelial cells: implications for pathogenesis of hyperacute rejection. J Exp Med 1990; 171: 1336–8
Good AH, Cooper DKC, Malcolm AJ, et al. Identification of carbohydrate structures that bind human antiporcine antibodies: implications for discordant xenografting in humans. Transplant Proc 1992; 24: 559–62
Platt JL, Lindman BJ, Chen H, et al. Endothelial cell antigens recognized by xenoreactive human natural antibodies. Transplantation 1990; 50: 817–22
Platt JL, Lindman BJ, Bach FH. Natural antibody targets on discordant endothelium: molecular characterization and consequences of antibody binding. Transplant Proc 1991; 23: 815–6
Turman MA, Casali P, Notkins AL, et al. Polyreactivity and antigen specificity of human xenoreactive monoclonal and serum natural antibodies. Transplantation 1991; 52: 710–7
Dabkowski PL, Vaughan HA, Mckenzie IFC, et al. Characterisation of a cDNA clone encoding the pig alpha 1,3 galactosyltransferase: implications for xenotransplantation. Transplant Proc 1993; 25: 2921
Galili U, Swanson K. Gene sequences suggest inactivation of alpha-l,3-galactosyltransferase in catarrhines after the divergence of apes from monkeys. Proc Natl Acad Sci USA 1991; 88: 7401–4
Galili U, Shohet SB, Korbin E, et al. Man, apes and old world monkeys differ from other mammals in the expression of α-galactosyl epitopes on nucleated cells. J Biol Chem 1988; 263: 17755–62
Galili U, Clark MR, Shohet SB, et al. Evolutionary relationship between natural anti-Gal antibody and the Gal α 1–3 Gal epitope in primates. Proc Natl Acad Sci USA 1987; 84: 1369–73
Rother RP, Fodor WL, Springhorn JP, et al. A novel mechanism of retrovirus inactivation in human serum mediated by antialpha-galactosyl natural antibody. J Exp Med 1995; 182: 1345–55
Galili U, Anaraki F, Thall A, et al. One percent of human circulating B lymphocytes are capable of producing the natural anti-Gal antibody. Blood 1993; 82: 2485–93
Galili U, Mandrell RE, Hamedeh RM, et al. Interaction between natural anti-α-galactosyl immunoglobulin G and bacteria of the human flora. Infection Immunity 1988; 56: 1730–7
Cooper DKC, Good AH, Ye Y, et al. Specific intravenous carbohydrate therapy: a new approach to the inhibition of antibody-mediated rejection following ABO-incompatible allografting and discordant xenografting. Transplant Proc 1993; 25: 377–8
Soares M, Latinne D, Elsen M, et al. Isotype characterization of rat preformed natural antibodies against guinea pig cells. Transplant Proc 1992; 24: 451–2
Sandrin MS, Vaughan HA, Dabkowski PL, et al. Anti-pig IgM antibodies in human serum react predominantly with Gal(αl-3) Gal epitopes. Proc Natl Acad Sci USA 1993; 90: 11391–5
Romanella M, Aminian A, Adam WR, et al. Involvement of both the classical and alternate pathways of complement in an ex vivo model of xenograft rejection. Transplantation 1997; 63: 1021–5
Mathieson PW, Fearon DT, Moore FD. Complement. In: Tilney NL, Strom TB, Paul LC, editors. Transplantation biology: cellular and molecular aspects. Piladelphia: Lippincott-Raven, 1996
Pruitt SK, Baldwin WM, Sanfilippo F. The role of C3a and C5a in hyperacute rejection of guinea pig-to-rat cardiac xenografts. Transplant Proc 1996; 28: 596
Pruitt SK, Baldwin WM, Marsh HC, et al. The effect of soluble complement receptor type-1 on hyperacute xenograft rejection. Transplantation 1991; 52: 868–73
Hancock WW, Blakely ML, Vanderwerf W, et al. Rejection of guinea pig cardiac xenografts post cobra venom factor therapy is associated with infiltration by mononuclear cells secreting interferon gamma and diffuse endothelial activation. Transplant Proc 1993; 25: 2932
Candinas D, Lesnikoski B A, Robson SC, et al. Soluble complement receptor type 1 and cobra venom factor in discordant xenotransplantation. Transplant Proc 1996; 28: 581
Somerville CA, Kyriazis AG, McKenzie M, et al. Functional expression of human CD59 in transgenic mice. Transplantation 1994; 58: 1430–5
Murray AG, Khodadoust MM, Pober JS, et al. Porcine aortic endothelial cells activate human T cells: direct presentation of MHC antigens and costimulation by ligands for human CD2 and CD28. Immunity 1994; 1: 57–63
Goodman DJ, Vonalbertini M, Mcshea A, et al. Adenoviral mediated overexpression of IκBα in endothelial cells inhibits natural killer cell-mediated endothelial cell activation. Trans- plantation 1997; 62: 967–72
Hemmi S, Bohni R, Stark G, et al. A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells. Cell 1994; 76: 803–9
Platt JL, Lindman BJ, Geller RL, et al. The role of natural antibodies in the activation of xenogenic endothelial cells. Transplantation 1991; 52: 1037–43
Lindman BJ, Noreen HJ, Geller RL, et al. The role of cell surface glycoproteins in the activation of endothelial cells by antibody and complement. Transplant Proc 1992; 24: 586–7
Geller RL, Bach FH, Vercellotti GM, et al. Activation of endothelial cells in hyperacute xenograft rejection. Transplant Proc 1992; 24: 592
Pober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation 1991; 50: 537–43
Robson SC, Kaczmarek E, Siegel JB, et al. Loss of ATP diphosphohydrolase activity with endothelial cell activation. J Exp Med 1997; 185(1): 153–63
Esmon CT. Cell-mediated events that control blood coagulation and vascular injury. Annu Rev Cell Biol 1993; 9: 1–26
Hofer E, Stuhlmeier KM, Blakely ML, et al. Pathways of procoagulation in discordant xenografting. Transplant Proc 1994; 26: 1322
Bach FH, Robson SC, Ferran C, et al. Endothelial cell activation and thromboregulation during xenograft rejection. Immunol Rev 1994; 141: 5–30
Moll T, Czyz M, Holzmuller H, et al. Regulation of the tissue factor promoter in endothelial cells: binding of NFκB-, AP-1-and Spl-like transcription factors. J Biol Chem 1995; 270: 3849–57
Blakely ML, Vanderwerf WJ, Berndt MC, et al. Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection. Transplantation 1994; 58: 1059–66
Grey S, Tsuchida A, Hau H. Selective inhibitory efects of the anticoagulant activated protein C on the response of human mononuclear phagocytes to lipopolysaccharide, interferongamma or phorbol ester. J Immunol 1994; 153: 3664–71
Hancock WW, Salem HH. Activated protein C blocks endotoxin-induced renal injury: reduction in cytokine expression, endothelial cell activation, fibrin deposition and cellular infiltration. J Am Soc Nephrol 1993; 4: 605–6
Pareti FI, Mazzucato M, Bottini E, et al. Interaction of porcine von Willebrand factor with the platelet glycoproteins Ib and IIb/IIIa complex. Br J Haematol 1992; 82: 81–5
Siems W, Grune T, Lehman C. Superoxide dismutase promotes ATP and GTP restoration of rat small intestine during postischaemic reperfusion. Pharmazie 1991; 46: 735–7
Kelly KJ, Williams WW, Colvin RB, et al. Antibody to intercellular adhesion molecule-1 protects the kidney against ischaemic injury. Proc Natl Acad Sci USA 1994; 91: 812–6
Palmiter RD, Brinster RL. Transgenic mice. Cel l 1985; 41: 343–5
Vandenderen BJW, Pearse MJ, d’Apice AJF. The prospects for renal xenotransplantation. Nephrology 1996; 2: 217–28
Tange M, Tearle R, Katerelos M, et al. Analysis of alpha 1,3-galactosyltransferase knockout mice. Transplant Proc 1996; 28: 620–1
Cowan PJ, Shinkel TA, Witort EJ, et al. Targeting gene expression to endothelial cells in transgenic mice using the human intercellular adhesion molecule 2 promoter. Transplantation 1996; 62: 155–60
Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 1992; 89: 5547–51
Yannoutsos N, Langford GA, Cozzi E, et al. Production of pigs transgenic for human regulators of complement activation. Transplant Proc 1995; 27: 324–5
Cooper DKC, Ye Y, Niekrasz M, et al. Specific intravenous carbohydrate therapy: a new concept in inhibiting antibody-mediated rejection experience with ABO-incompatible cardiac allografting in the baboon. Transplantation 1993; 56: 769–77
Chen C-G, Fisicaro N, Shinkel TA, et al. Reduction in Gal-αl,3-Gal epitope expression in transgenic mice expressing human H-transferase. Xenotransplantation 1996; 3: 69–75
Sandrin MS, Mouhtouris E, Osman N, et al. Elimination of the major porcine xenoantigen, Gal α(l,3) Gal, by expression of α(l,2) fucosyltransferase. Glycoconjugate J 1995; 12: 468
d’Apice AJF, Tange MJ, Chen GC, et al. Two genetic approaches to the galactose alpha 1,3 galactose xenoantigen. Transplant Proc 1996; 28: 540
Sharma A, Okabe J, Birch P, et al. Reduction in the level of Gal(alpha l,3)Gal in transgenic mice and pigs by the expression of an alpha(l,2)fucosyltransferase. Proc Natl Acad Sci USA 1996; 93: 7190–5
Dalmasso AP, Vercellotti GM, Platt JL, et al. Inhibition of complement-mediated endothelial cell cytotoxicity by decay-accelerating factor: potential for prevention of xenograft hyperacute rejection. Transplantation 1991; 52: 530–3
Dalmasso AP, Vercellotti GM, Fischel RJ, et al. Mechanism of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients. Am J Pathol 1992; 140: 1157–66
Loveland BE, Johnstone RW, Russell SM, et al. CD46 (MCP) confers protection from lysis by xenogeneic antibodies. Transplant Proc 1993; 25: 396–7
van Denderen BJ, Pearse MJ, Aminian A, et al. Decay-accelerating factor transgenic mouse hearts are protected from human complement-mediated attack. Transplant Proc 1996; 28: 583–4
Mora M, Mulder LCF, Lazzeri M, et al. Protection from complement-mediated injury in livers and kidneys of transgenic mice expressing human complement regulators. Xenotransplantation 1996; 3: 63–8
Van Denderen BJW, Pearse MJ, Nottle MB, et al. Expression of functional decay-accelerating factor (CD55) in transgenic mice protects against human complemet-mediated attack. Transplantation 1996; 61: 582–8
Cowan PJ, Somerville CA, Shinkel TA, et al. High-level endothelial expression of human CD59 prolongs heart function in an ex vivo model of xenograft rejection. Transpianation 1998;. In press
Cozzi E, Langford GA, Richards A, et al. Expression of human decay accelerating factor in transgenic pigs. Transplant Proc 1994; 26: 1402–3
McCurry KR, Kooyman DL, Alvarado CG, et al. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury. Nature Med 1995; 1: 423–7
Goodman DJ, Vonalbertini M, Willson A, et al. Direct activation of porcine endothelial cells by human natural killer cells. Transplantation 1996; 61: 763–71
Bach FH, Winkler H, Ferran C, et al. Delayed xenograft rejection. Immunol Today 1996; 17: 379–84
Stroka DM, Cooper JT, Brostjan C, et al. Expression of a negative dominant mutant of human p55 tumor necrosis factor receptor inhibits TNF and monocyte-induced activation in porcine aortic endothelial cells. Transplant Proc 1997; 29(1-2): 882
Wrighton CJ, Kopp CW, Mcshea A, et al. High-level expression of functional human thrombomodulin in cultured porcine aortic endothelial cells. Transplant Proc 1995; 27: 288–9
Inverardi L, Samaja M, Motterlini R, et al. Early recognition of a discordant xenogeneic organ by human circulating lymphocytes. J Immunol 1992; 149: 1416–23
Ferran C, Millan MT, Csizmadia V, et al. Inhibition of NF-kB by pyrrolidine dithiocarbamate blocks endothelial cell activation. Biochem Biophys Res Commun 1995; 214: 212–23
Baeuerle PA, Baltimore D. NF-κB: ten years after. Cell 1996; 87: 13–20
de Martin R, Vanhove B, Cheng Q, et al. Cytokine-inducible expression in endothelial cells of an IκBα-like gene is regulated by NFκB. EMBO J 1993; 12: 2773–9
Wrighton CJ, Hofer-Warbinek R, Moll T, et al. Inhibition of endothelial cell activation by adenovirus-mediated expression of IκBα, an inhibitor of the transcription factor NF-κB. J Exp Med 1996; 183: 1013–22
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Goodman, D.J., Pearse, M.J. & d’Apice, A.J.F. Overcoming Hyperacute Xenograft Rejection With Transgenic Animals. BioDrugs 9, 219–234 (1998). https://doi.org/10.2165/00063030-199809030-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00063030-199809030-00005