, Volume 10, Issue 2, pp 111–121 | Cite as

Potential of Anticomplement Therapy in Clinical Transplantation

  • Timothy J. Kroshus
  • R. Morton BolmanIII
  • Agustin P. Dalmasso
Review Article Immunological Disorders


The activation of complement contributes to tissue damage in many ways. Prevention of complement activation in organ transplantation has largely centred on studies in xenotransplantation, where complement plays a key role in the pathogenesis of hyperacute rejection. Transgenic porcine organs expressing human regulators of complement activation in combination with soluble inhibitors as well as appropriate immunosuppression may be sufficient to alleviate the major immunological barriers that currently prevent the use of xenogeneic organs for human transplantation.


Adis International Limited Complement Activation Membrane Attack Complex Complement Inhibitor Hyperacute Rejection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Dalmasso AP. The complement system in xenotransplantation. Immunopharmacology 1992; 24: 149–60PubMedCrossRefGoogle Scholar
  2. 2.
    Hasan R, Van der Bogaerde J, Forty J, et al. Xenograft adaptation is dependent on the presence of antispecies antibody, not prolonged residence in the recipient. Transplant Proc 1992; 24: 531–2PubMedGoogle Scholar
  3. 3.
    Lawson JH, Platt JL. Molecular barriers in xenotransplantation. Transplantation 1996; 62: 303–10PubMedCrossRefGoogle Scholar
  4. 4.
    Bach FH, Winkler H, Ferran C, et al. Delayed xenograft rejection. Immunol Today 1996; 17: 379–84PubMedCrossRefGoogle Scholar
  5. 5.
    Dalmasso AP. Complement in the pathophysiology and diagnosis of human diseases. Crit Rev Clin Lab Sci 1986; 24:123–83PubMedCrossRefGoogle Scholar
  6. 6.
    Muller-Eberhard HJ. Complement: chemistry and pathways. In: Gallin JI, Golgstein IM, Snyderman R, editors. Inflammation: basic principles and clinical correlates. New York: Raven Press, 1992: 33Google Scholar
  7. 7.
    Dalmasso AP, Benson BA. Pore size of lesions induced by complement on red cell membranes and its relation to C5b-8, C5b-9 and poly C9. In: Podack ER, editor. Cytolytic lymphocyte clones and complement as effectors of the immune system. Boca Raton: CRC Press, 1988: 207Google Scholar
  8. 8.
    Morgan BP. Cellular responses to the membrane attack complex. In: Whaley K, Loos M, Weiler J, editors. Immunology and medicine. Vol 20. Dordrecht: Kluwer Academic, 1993: 325Google Scholar
  9. 9.
    Jefferson KP, Tyerman KS, McLeish M, et al. Donor pretreatment prolongs survival of discordant xenografts. Transplant Proc 1991; 23: 2280–1PubMedGoogle Scholar
  10. 10.
    Chartrand C, O’Regan S, Robitaille P, et al. Delayed rejection of cardiac xenografts in C6-deficient rabbits. Immunology 1979; 38: 245–8PubMedGoogle Scholar
  11. 11.
    Zhow XJ, Niesen N, Pawlowski I, et al. Prolongation of survival of discordant kidney xenograft by C6 deficiency. Transplantation 1990; 50: 896–98PubMedCrossRefGoogle Scholar
  12. 12.
    Brauer RB, Baldwin WMI, Daha MR, et al. Use of C6-deficient rats to evaluate the mechanism of hyperacute rejection of discordant cardiac xenografts. J Immunol 1993; 151: 7240–8PubMedGoogle Scholar
  13. 13.
    Dalmasso AP, Vercellotti GM, Fischel RJ, et al. Mechanism of complement activation in the hyperacute rejection of porcine xenografts transplanted into primate recipients. Am J Pathol 1992; 140: 1157–66PubMedGoogle Scholar
  14. 14.
    Platt JL, Lindman BJ, Geller RL, et al. The role of natural antibodies in the activation of xenogenic endothelial cells. Transplantation 1991; 52: 1037–43PubMedCrossRefGoogle Scholar
  15. 15.
    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: 2887–90PubMedCrossRefGoogle Scholar
  16. 16.
    Platt JL, Fischel RJ, Matas AJ, et al. Immunopathology of hyperacute xenograft rejection in a swine to primate model. Transplantation 1991; 52: 214–20PubMedCrossRefGoogle Scholar
  17. 17.
    Vanhove B, de Martin R, Lipp J, et al. Human xenoreactive natural antibodies of the IgM isotype activate pig endothelial cells. Xenotransplantation 1994; 1: 17–22CrossRefGoogle Scholar
  18. 18.
    Tuso PJ, Cramer DV, Middleton YD, et al. Pig aortic endothelial cell antigens recognized by human IgM natural antibodies. Transplantation 1993; 56: 651–5PubMedCrossRefGoogle Scholar
  19. 19.
    Schaapherder AFM, Gooszen HG, Te Bulte MTJW, et al. Human complement activation via the alternative pathway on porcine endothelium initiated by IgA antibodies. Transplantation 1995; 60: 287–91PubMedCrossRefGoogle Scholar
  20. 20.
    Kroshus TJ, Bolman RM, Dalmasso AP. Selective IgM depletion prolongs organ survival in an ex vivo model of pig-to-human xenotransplantation. Transplantation 1996; 62: 5–12PubMedCrossRefGoogle Scholar
  21. 21.
    Miyagawa S, Shirakura R, Matsumiya G, et al. Prolonging discordant xenograft survival with anticomplement reagents K76COOH and FUT175. Transplantation 1993; 55: 709–13PubMedCrossRefGoogle Scholar
  22. 22.
    Dalmasso AP, Platt JL. Prevention of complement-mediated activation of xenogeneic endothelial cells in an in vitro model of xenograft hyperacute rejection by C1 inhibitor. Transplantation 1993; 56: 1171–6PubMedCrossRefGoogle Scholar
  23. 23.
    Dalmasso AP, Platt JL. Potentiation of C1 inhibitorplus heparin in prevention of complement-mediated activation of endothelial cells in a model of xenograft hyperacute rejection. Transplant Proc 1994; 26: 1246–7PubMedGoogle Scholar
  24. 24.
    Stevens RB, Wang YL, Kaji H, et al. Administration of non-anticoagulant heparin inhibits the loss of glycosaminoglycans from xenogeneic cardiac grafts and prolongs graft survival. Transplant Proc 1993; 25: 382PubMedGoogle Scholar
  25. 25.
    Weisman HF, Bartow T, Leppo MK, et al. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 1990; 249: 146–51PubMedCrossRefGoogle Scholar
  26. 26.
    Pruitt SK, Baldwin WM, Marsh HC, et al. The effect of soluble complement receptor type 1 on hyperacute xenograft rejection. Transplantation 1991; 52: 868–73PubMedCrossRefGoogle Scholar
  27. 27.
    Xia W, Fearon DT, Moore FD, et al. Prolongation of guinea pig cardiac xenograft survival in rats by soluble human complement receptor type 1. Transplant Proc 1992; 24: 479–80PubMedGoogle Scholar
  28. 28.
    Pruitt SK, Kirk AD, Bollinger RR, et al. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation 1994; 57: 363–70PubMedCrossRefGoogle Scholar
  29. 29.
    Pruitt SK, Bollinger RR, Collins BH, et al. Continuous complement (C) inhibition using soluble C receptor type 1 (sCR1): effect on hyperacute rejection of pig-to-primate cardiac xenografts. Transplant Proc 1996; 28: 756PubMedGoogle Scholar
  30. 30.
    Ryan US. Complement inhibitory therapeutics and xenotransplantation. Nature Med 1995; 1: 967–8PubMedCrossRefGoogle Scholar
  31. 31.
    Christiansen D, Milland J, Thorley BR, et al. Engineering of recombinant soluble CD46: an inhibitor of complement activation. Immunology 1996; 87: 348–54PubMedGoogle Scholar
  32. 32.
    Higgins PJ, Ko JL, Lobell R, et al. A soluble chimeric complement inhibitory protein that possesses both decay-accelerating and Factor I cofactor activities. J Immunol 1997; 158: 2872–81PubMedGoogle Scholar
  33. 33.
    Vogel CW, Muller-Eberhard HJ. The cobra venom factor-dependent C3 convertase of human complement. J Biol Chem 1982; 257: 8292–9PubMedGoogle Scholar
  34. 34.
    Leventhal JR, Dalmasso AP, Cromwell JW, et al. Prolongation of cardiac xenograft survival by depletion of complement. Transplantation 1993; 55: 857–65PubMedCrossRefGoogle Scholar
  35. 35.
    Leventhal JR, Matas AJ, Sun LH, et al. The immunopathology of cardiac xenograft rejection in the guinea pig-to-rat model. Transplantation 1993; 56: 1–8PubMedCrossRefGoogle Scholar
  36. 36.
    Johnson EM, Leventhal JR, Dalmasso AP, et al. Inactivation of C3 and C5 prolongs cardiac xenograft survival and decreases leukocyte infiltration in a model of delayed xenograft rejection. Transplant Proc 1996; 28: 603PubMedGoogle Scholar
  37. 37.
    Leventhal JR, Sakiyalak P, Witson J, et al. The synergistic effect of combined antibody and complement depletion on discordant xenograft survival in nonhuman primates. Transplantation 1994; 57: 974–8PubMedCrossRefGoogle Scholar
  38. 38.
    Leventhal JR, John R, Fryer JP, et al. Removal of baboon and human anti-porcine IgG and IgM natural antibodies by immunoadsorption: results of in vitro and in vivo studies. Transplantation 1995; 59: 294–300PubMedGoogle Scholar
  39. 39.
    Ronda N, Hurez V, Kazatchkine MD. Intravenous immunoglobulin therapy of autoimmune and systemic inflammatory diseases. Vox Sang 1993; 64: 65–72PubMedCrossRefGoogle Scholar
  40. 40.
    Kohsaka T, Abe J, Ashina T, Kobayashi N. Classical pathway complement activation in Kawasaki syndrome. J Allergy Clin Immunol 1994; 93: 520–5PubMedCrossRefGoogle Scholar
  41. 41.
    Newburger JW, Takahashi M, Barns JC, et al. The treatment of Kawasaki syndrome with intravenous gamma globulin. N Engl J Med 1986; 315: 341–7PubMedCrossRefGoogle Scholar
  42. 42.
    Basta M, Kirshbom P, Frank MM, et al. Mechanism of therapeutic effect of high-dose intravenous immunoglobulin: attenuation of acute, complement-dependent immune damage in a guinea pig model. J Clin Invest 1989; 84: 1974–81PubMedCrossRefGoogle Scholar
  43. 43.
    Magee JC, Collins BH, Harland RC, et al. Immunoglobulin prevents complement-mediated hyperacute rejection in swine-to-primate xenotransplantation. J Clin Invest 1995; 96: 2404–12PubMedCrossRefGoogle Scholar
  44. 44.
    Frank MM, Basta M, Fries LF. The effects of intravenous immune globulin on complement-dependent immune damage of cells and tissues. Clin Exp Immunol Immunopathol 1992; 62: S82–6CrossRefGoogle Scholar
  45. 45.
    Basta M, Langlois PF, Marques M, et al. High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance. Blood 1989; 74: 326–33PubMedGoogle Scholar
  46. 46.
    Miletic VD, Hester CG, Frank MM. Regulation of complement activity by immunoglobulin. J Immunol 1996; 156: 749–57PubMedGoogle Scholar
  47. 47.
    Basta M, Fries LF, Frank MM. High doses of intravenous Ig inhibit in vitro uptake of C4 fragments onto sensitized erythrocytes. Blood 1991; 77: 376–80PubMedGoogle Scholar
  48. 48.
    Lutz HU, Stammler P, Jelezarova E, et al. High doses of immunoglobulin G attenuate immune aggregate-mediated complement activation by enhancing physiologic cleavage of C3b in C3bn-complexes. Blood 1996; 88: 184–93PubMedGoogle Scholar
  49. 49.
    Latremouille C, Haeffner-Cavaillon N, Goussef N, et al. Normal human polyclonal immunoglobulins for intravenous use significantly delay hyperacute xenograft rejection. Transplant Proc 1994; 26: 1285PubMedGoogle Scholar
  50. 50.
    Gautreau C, Kojima T, Woimant G, et al. Use of intravenous immunoglobulin to delay xenogeneic hyperacute rejection: an in vivo and in vitro evaluation. Transplantation 1995; 60: 903–7PubMedGoogle Scholar
  51. 51.
    Tyan DB, Li VA, Czer L, et al. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. Transplantation 1994; 57: 553–62PubMedGoogle Scholar
  52. 52.
    McIntyre JA, Higgins N, Britton R, et al. Utilization of intravenous immunoglobulin to ameliorate alloantibodies in a highly sensitized patient with a cardiac assist device awaiting heart transplantation. Transplantation 1996; 62: 691–3PubMedCrossRefGoogle Scholar
  53. 53.
    Matis LA, Rollins SA. Complement-specific antibodies: designing novel anti-inflammatories. Nature Med 1995; 1: 839–42PubMedCrossRefGoogle Scholar
  54. 54.
    Kroshus TJ, Rollins SA, Dalmasso AP, et al. Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation. Transplantation 1995; 60: 1194–202PubMedGoogle Scholar
  55. 55.
    Rollins SA, Matis LA, Springhorn JP, et al. Monoclonal antibodies directed against human C5 and C8 block complement-mediated damage of xenogeneic cells and organs. Transplantation 1995; 60: 1284–92PubMedGoogle Scholar
  56. 56.
    Hourcade D, Holers VM, Atkinson JP. The regulators of complement activation (RCA) gene cluster. Adv Immunol 1989; 45: 381–416PubMedCrossRefGoogle Scholar
  57. 57.
    Atkinson JP, Oglesby TJ, Whit D, et al. Separation of self from non-self in the complement system: a role for membrane cofactor protein and decay accelerating factor. Clin Exp Immunol 1991; 86 S1: 27–30PubMedCrossRefGoogle Scholar
  58. 58.
    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: 530–3PubMedCrossRefGoogle Scholar
  59. 59.
    Oglesby TJ, Allen CJ, Liszewski MK, et al. Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism. J Exp Med 1992; 175: 1547–51PubMedCrossRefGoogle Scholar
  60. 60.
    Zhao J, Rollins SA, Maher SE, et al. Amplified gene expression in CD59-transfected Chinese hamster ovary cells confers protection against the membrane attack complex of human complement. J Biol Chem 1991; 266: 13418–22PubMedGoogle Scholar
  61. 61.
    Akami T, Sawada R, Minato N, et al. Cytoprotective effect of CD59 antigen on xenotransplantation immunity. Transplant Proc 1992; 24: 485–7PubMedGoogle Scholar
  62. 62.
    Charreau B, Cassard A, Tesson L, et al. Protection of rat endothelial cells from primate complement-mediated lysis by expression of human CD59 and/or decay-accelerating factor. Transplantation 1994; 58: 1222–9PubMedGoogle Scholar
  63. 63.
    Kennedy SP, Rollins SA, Burton WV, et al. Protection of porcine aortic endothelial cells from complement-mediated cell lysis and activation by recombinant human CD59. Transplantation 1994; 57: 1494–501PubMedGoogle Scholar
  64. 64.
    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: 423–7PubMedCrossRefGoogle Scholar
  65. 65.
    Fodor WL, Williams BL, Matis LA, et al. Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. Proc Natl Acad Sci USA 1994; 91: 11153–7PubMedCrossRefGoogle Scholar
  66. 66.
    Rosengard AM, Cary NRB, Langford GA, et al. Tissue expression of human complement inhibitor, decay-accelerating factor, in transgenic pigs: a potential for preventing xenograft rejection. Transplantation 1995; 59: 1325–33PubMedGoogle Scholar
  67. 67.
    Somerville CA, Kyriazias AG, McKenzie A, et al. Functional expression of human CD59 in transgenic mice. Transplantation 1994; 58: 1430–5PubMedGoogle Scholar
  68. 68.
    Mulder LCF, Mora M, Lazzeri M, et al. Human MCP and DAF double transgenic mice are completely protected from human complement attack in an in vivo model. Transplant Proc 1996; 28: 589PubMedGoogle Scholar
  69. 69.
    Longford GA, Cozzi E, Yannoutsos N, et al. Production of pigs transgenic for human regulators of complement activation using YAC technology. Transplant Proc 1996; 28: 862–3Google Scholar
  70. 70.
    Kroshus TJ, Bolman RM, Dalmasso AP, et al. Expression of human CD59 in transgenic pig organs enhances organ survival in an ex vivo xenogeneic perfusion model. Transplantation 1996; 61: 1513–21PubMedCrossRefGoogle Scholar
  71. 71.
    Sandrin MS, Vaughn HA, Dabkowski PL, et al. Anti-pig IgM antibodies in human serum react predominantly with Gal(1–3)Gal epitopes. Proc Natl Acad Sci USA 1993; 90: 11391–5PubMedCrossRefGoogle Scholar
  72. 72.
    Cowan PJ, Shinkel TA, Witort E, et al. Targeting gene expression to endothelial cells in transgenic mice using the human intracellular adhesion molecule 2 promoter. Transplantation 1996; 62: 155–60PubMedCrossRefGoogle Scholar
  73. 73.
    Fodor WL, Rollins SA, Guilmette ER, et al. A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex. J Immunol 1995; 155: 4135–8PubMedGoogle Scholar
  74. 74.
    Tucker AW, Davies HS, Carrington CA, et al. The fertility and breeding potential of boars expressing a functional regulator of human complement activation. Transplant Proc 1996; 28: 642PubMedGoogle Scholar
  75. 75.
    Pascual M, French LE. Complement in human diseases: looking towards the 21st century. Immunol Today 1995; 16: 58–61PubMedCrossRefGoogle Scholar
  76. 76.
    Morgan BP. Effects of membrane attack complex of complement on nucleated cells. Curr Top Microbiol Immunol 1992; 178: 115–40PubMedCrossRefGoogle Scholar
  77. 77.
    Pemberton M, Anderson G, Vetvicka V, et al. Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle. J Immunol 1993; 150: 5104–13PubMedGoogle Scholar
  78. 78.
    Maroko PR, Carpenter CD, Chiariello M, et al. Reduction by cobra venom factor of myocardial necrosis after coronary artery occlusion. J Clin Invest 1978; 61: 661–70PubMedCrossRefGoogle Scholar
  79. 79.
    Linas SL, Whittenburg D, Parsons PE, et al. Mild renal ischemia activates primed neutrophils to cause acute renal failure. Kidney Int 1992; 42: 610–6PubMedCrossRefGoogle Scholar
  80. 80.
    Weiler JM, Edens RE, Linhardt RJ, et al. Heparin and modified heparin inhibit complement activation in vivo. J Immunol 1992; 148: 3210–5PubMedGoogle Scholar
  81. 81.
    Weiler JM, Lindardt RJ. Comparison of the activity of polyanions and polycations on the classical and alternative pathways of complement. Immunopharmacology 1989; 17: 65–72PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1998

Authors and Affiliations

  • Timothy J. Kroshus
    • 1
  • R. Morton BolmanIII
    • 1
  • Agustin P. Dalmasso
    • 1
  1. 1.Departments of Surgery and Laboratory Medicine and PathologyUniversity of Minnesota and the Veterans Affairs Medical CenterMinneapolisUSA

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