, Volume 15, Issue 8, pp 491–500 | Cite as

Co-Stimulatory Blockade and Tolerance Induction in Transplantation

Leading Article


Recipients of organ and tissue transplants require lifelong immunosuppression to prevent rejection. Better understanding of the processes culminating in allograft rejection has led to novel approaches to modulating the immune response. Co-stimulatory signals between antigen-presenting and -responding cells are essential for a normal alloimmune response, and blockade of these pathways during initial graft-host interaction may be used to ameliorate or prevent a destructive response from proceeding. A large number of experimental studies now support this concept, and early clinical trials have been initiated. Despite some early difficulties and many unanswered questions, co-stimulatory blockade has major potential as a future immune-modulating mechanism for use in clinical transplantation.



This work was supported in part by grants from the Health Research Council (HRC) of New Zealand and the Auckland Medical Research Foundation (AMRF).


  1. 1.
    Sayegh M, Turka L. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998; 338(25): 1813–21PubMedCrossRefGoogle Scholar
  2. 2.
    Bretscher P. The two signal model of lymphocyte activation twenty-one years later. Iimmunol Today 1992; 13: 74–6CrossRefGoogle Scholar
  3. 3.
    Laffety K. A few steps along the path to adult transplantation tolerance. Transplant Proc 1999; 31 Suppl.1/2A: S11–3CrossRefGoogle Scholar
  4. 4.
    Bluestone J, Khattri R, Seventer GV. Accessory molecules. 4th ed. Piladelphia: Lippincott-Raven, 1999Google Scholar
  5. 5.
    Lenschow D, Walunas T, Bluestone J. CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996; 12: 233–58CrossRefGoogle Scholar
  6. 6.
    Thompson C. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell differentiation? Cell 1995; 81(7): 979–82PubMedCrossRefGoogle Scholar
  7. 7.
    Shahinian A, Pfeffer K, Lee K, et al. Differential T cell costimulatiory requirements in CD28-deficient mice. Science 1993; 261: 609–12PubMedCrossRefGoogle Scholar
  8. 8.
    Wulfing C, Davis M. A receptor/cytoskeletal movement triggered by costimulation during Tcell activation. Science 1998; 282: 2266–9PubMedCrossRefGoogle Scholar
  9. 9.
    Sperling A, Bluestone J. The complexities of T-cell co-stimulation: CD28 and beyond. Immunol Rev 1996; 153: 155–82PubMedCrossRefGoogle Scholar
  10. 10.
    Hollander C, Zuklys S, Forster E, et al. On costimulatory signals and T cell tolerance: relevance for transplantation. Transplant Proc 1999; 31 Suppl.1/2A: S25–S32CrossRefGoogle Scholar
  11. 11.
    Brunet J, Denizot F, Luciani M, et al. A new member of the immunoglobulin superfamily-CTLA-4. Nature 1987; 328: 267–70PubMedCrossRefGoogle Scholar
  12. 12.
    Harper K, Balzano C, Rouvier E, et al. CTLA4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence message expression, gene structure, and chromosomal location. J Immunol 1991; 147(3): 1037–44PubMedGoogle Scholar
  13. 13.
    Linsley P, Greene J, Tan P, et al. Coexpression and functional cooperation of CTLA4 and CD28 on activated T lymphocytes. J Exp Med 1992; 176: 1595–604PubMedCrossRefGoogle Scholar
  14. 14.
    Lee K, Chuang E, Griffin M, et al. Molecular basis of T cell inactivation by CTLA-4. Science 1998; 282: 2263–6PubMedCrossRefGoogle Scholar
  15. 15.
    Walunas T, Bluestone J. CTLA4 regulates tolerance induction and T cell differentiation in vivo. J Immunol 1998; 160: 3855–60PubMedGoogle Scholar
  16. 16.
    Walunas T, Bakker C, Bluestone J. CTLA4 ligation blocks CD28 dependent T cell activation. J Exp Med 1996; 183: 2541–50PubMedCrossRefGoogle Scholar
  17. 17.
    Tivol E, Boyd S, McKeon S, et al. CTLA4Ig prevents lymphoproliferation and fatal multiorgan destruction in CTLA4 deficient mice. J Immunol 1997; 158: 5091–4PubMedGoogle Scholar
  18. 18.
    Hutloff A, Dittrich AM, Beier KC, et al. ICOS as an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 1999; 397: 263–6PubMedCrossRefGoogle Scholar
  19. 19.
    Clark L, Foy T, Noelle R. CD40 and its ligand. Adv Immunol 1996; 63: 43–78PubMedCrossRefGoogle Scholar
  20. 20.
    Grewal I, Flavell R. The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 1996; 153: 85–106PubMedCrossRefGoogle Scholar
  21. 21.
    Armitage R, Fanslow W, Stockbine L, et al. Molecular and biological characterisation of a murine ligand for CD40. Nature 1992; 357: 80–2PubMedCrossRefGoogle Scholar
  22. 22.
    Hermann P, Blanchard D, de Saint-Vis B, et al. Expression of a 32-kDa ligand for the CD40 antigen on activated human T lymphocytes. Eur J Immunol 1993; 23: 961–4PubMedCrossRefGoogle Scholar
  23. 23.
    Lane P, Traunecker A, Hubele S, et al. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. Eur J Immunol 1992; 22: 2573–8PubMedCrossRefGoogle Scholar
  24. 24.
    Noelle R, Roy M, Shepherd D, et al. A 39-kDa protein on activated helper T cell binds CD40 and transduces the signal for cognate activation on B cells. Proc Natl Acad Sci USA 1992; 89: 6550–4PubMedCrossRefGoogle Scholar
  25. 25.
    Grewal I, Flavell R. CD40 and CD154 in cell mediated immunity. Annu Rev Immunol 1998; 16: 111–35PubMedCrossRefGoogle Scholar
  26. 26.
    Allen R, Armitage R, Conley M. CD40 ligand gene defects responsible for X-linked hyper IgM syndrome. Science 1993; 259: 990–3PubMedCrossRefGoogle Scholar
  27. 27.
    Ameratunga R, Lederman H, Sullivan K, et al. Defective antigen induced lymphocyte proliferation in X-linked hyper-IgM syndrome. J Pediatr 1997; 131: 147–50PubMedCrossRefGoogle Scholar
  28. 28.
    Stout R, Suttles J, Xu J, et al. Impaired T cell mediated macrophage activation in CD40 ligand deficient mice. J Immunol 1996; 156: 8–11PubMedGoogle Scholar
  29. 29.
    Ranheim E, Kipps T. Activated T cells induce expression of B7/BB1 on normal or leukaemic B cells through a C40 dependent signal. J Exp Med 1993; 177: 925–35PubMedCrossRefGoogle Scholar
  30. 30.
    Caux C, Massacrier B, Banbervliet B, et al. Activation of human dedritic cells through CD40 cross-linking. J Exp Med 1994; 180: 1263–72PubMedCrossRefGoogle Scholar
  31. 31.
    Stuber E, Strober W, Neurath M. Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med 1996; 183: 693–8PubMedCrossRefGoogle Scholar
  32. 32.
    Yellin M, Winikoff S, Fortune S, et al. Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) upregulation, IL-6 production and proliferation. J Leukoc Biol 1995; 58: 209–16PubMedGoogle Scholar
  33. 33.
    Durie F, Foy T, Masters S, et al. The role of CD40 in the regulation of humoral and cell mediated immunity. Immunol Today 1994; 15:406–11PubMedCrossRefGoogle Scholar
  34. 34.
    Hackett C, Dickler H. Immunologic tolerance for immune system-mediated diseases. J Allergy Clin Immunol 1999; 103: 362–70PubMedCrossRefGoogle Scholar
  35. 35.
    Koch F, Stanzyl U, Jennewein P, et al. High level IL12 production by murine dendritic cells: upregulation via MHC class II and CD40 molecules and downregulation by IL4 and IL10. J Exp Med 1996; 184:741–6PubMedCrossRefGoogle Scholar
  36. 36.
    Shu U, Kiniwa M, Wu C, et al. Activation of T cells induces interleukin-12 production by monocytes via CD40-CD40 ligand interactions. Eur J Immunol 1995; 25: 1125–8PubMedCrossRefGoogle Scholar
  37. 37.
    Hayashi T, Rao S, Meylan P, et al. Role of CD40 ligand in Mycobacterium avium infection. Infect Immun 1999; 67(7): 3558–65PubMedGoogle Scholar
  38. 38.
    Soong L, Xu J, Grewal I, et al. Disruption of CD40-CD40 ligand interaction results in an enhanced susceptibility to Leishmania amazonesis infection. Immunity 1996; 4: 263–73PubMedCrossRefGoogle Scholar
  39. 39.
    Hancock W, Sayegh M, Zheng X, et al. Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection. Proc Natl Acad Sci USA 1996; 93: 13967–72PubMedCrossRefGoogle Scholar
  40. 40.
    Larsen C, Alexander D, Hollenbaugh D, et al. CD40-gp39 interactions play a critical role during allograft rejection. Transplantation 1996; 61(1):4–9PubMedCrossRefGoogle Scholar
  41. 41.
    Kirk A, Harlan D, Armstrong N, et al. CTLA4Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94: 8789–94PubMedCrossRefGoogle Scholar
  42. 42.
    Gilfillan M, Noel P, Podack E, et al. Expression of the costimulatory receptor CD30 is regulated by both CD28 and cytokines. J Immunol 1998; 160(5): 2180–7PubMedGoogle Scholar
  43. 43.
    Hintzen R, Lens S, Lammers K, et al. Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation. J Immunol 1995; 154(6): 2612–23PubMedGoogle Scholar
  44. 44.
    Tan J, Ha J, Cho H, et al. Analysis of expression and function of the costimulatory molecule 4- 1BB in alloimune responses. Transplantation 2000; 70(1): 175–83PubMedGoogle Scholar
  45. 45.
    Josien R, Wong B, Li H, et al. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol 1999; 162: 2562–8PubMedGoogle Scholar
  46. 46.
    Gramaglia I, Weinberg A, Lemon M, et al. Ox-40 ligand: a potent costimulatory molecule sustaining primary CD4 T cell responses. J Immunol 1998; 161(12): 6510–7PubMedGoogle Scholar
  47. 47.
    Chapoval A, Ni J, Lau J, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Available from URL:
  48. 48.
    Abbas A, Sharpe A. T-cell stimulation: an abundance of B7s. Nat Med 1999; 5(12): 1345–6PubMedCrossRefGoogle Scholar
  49. 49.
    Damle N, Klussman K, Linsley P, et al. Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J Immunol 1992; 148(7): 1985–92PubMedGoogle Scholar
  50. 50.
    Damle N, Aruffo A. Vascular cell adhesion molecule-1 (VCAM-1) induces T-cell antigen receptor-dependent activation of CD4+ T lymphocytes. Proc Natl Acad Sci USA 1991; 88(15): 6403–7PubMedCrossRefGoogle Scholar
  51. 51.
    Biancone L, Segoloni G, Turello E, et al. Expression of inducible lymphocyte costimulatory molecules in human renal allograft. Nephrol Dial Transplant 1998; 13: 716–22PubMedCrossRefGoogle Scholar
  52. 52.
    Gaweco A, Wiesner R, Yong S, et al. CD40L expression in human liver allogafts during chronic ductopenic rejection. Liver Transpl Surg 1999; 5(1): 1–7PubMedCrossRefGoogle Scholar
  53. 53.
    Gaweco A, Mitchell B, Lucas B, et al. CD40 expression on graft infiltrates and parenchymal CD 154 (CD40L) induction in human chronic renal allograft rejection. Kidney Int 1999; 55: 1543–52PubMedCrossRefGoogle Scholar
  54. 54.
    Reul R, Fang J, Denton M, et al. CD40 and CD40 ligands are coexpressed on microvessels in vivo in human cardiac allograft rejection. Transplantation 1997; 64(12): 1765–74PubMedCrossRefGoogle Scholar
  55. 55.
    Zheng X, Schachter A, Vasconcellos L, et al. Increased CD40 ligand gene expression during human renal and murine islet allograft rejection. Transplantation 1998; 65(11): 1512–5PubMedCrossRefGoogle Scholar
  56. 56.
    Larsen C, Elwood E, Alexander D, et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 1996; 381: 434–8PubMedCrossRefGoogle Scholar
  57. 57.
    Kover K, Geng Z, Hess D, et al. CD40/CD40L (CD 154) blockade alone is sufficient to prevent islet allograft rejection in the rat [abstract no. 882]. American Society of Transplantation Eighteenth Annual Meeting; 1999 May 15–19; Chicago (IL)Google Scholar
  58. 58.
    Kirk A, Burkly L, Batty S, et al. Treatment with humanised monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med 1999; 5(6): 686–93PubMedCrossRefGoogle Scholar
  59. 59.
    Hancock W, Buelow R, Sayegh M, et al. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med 1998; 4(12): 1392–6PubMedCrossRefGoogle Scholar
  60. 60.
    Gordon E, Markees T, Phillips N, et al. Prolonged survival of rat islet and skin xenografts in mice treated with donor spenocytes and anti-CD 154 monoclonal antibody. Diabetes 1998; 47: 1199–206PubMedCrossRefGoogle Scholar
  61. 61.
    Bumgardner G, Li J, Gao D, eaet al. CD40L/CD40 costimulation in both CD4+ and CD8+ mediated immune responses to allogeneic hepatocytes [abstract no. 38]. The Sixth Basic Science Symposium of the Transplantation Society; 1999 Aug 25-29; Monterey (CA): 56Google Scholar
  62. 62.
    Bumgardner G, Li J, Heininger M, et al. Costimulation pathways in host immune responses to allogeneic hepatocytes. Transplantation 1998; 66(12): 1841–5PubMedCrossRefGoogle Scholar
  63. 63.
    Ha J, Bingaman A, Pearson T, et al. CD8+ T cells mediate aggressive skin allograft rejection in CD28-/- mice independent of the CD40/CD40Lcostimulatory pathway [abstract no. 39]. The Sixth Basic Science Symposium of the Transplantation Society; 1999 Aug 25–29; Monterey (CA): 57Google Scholar
  64. 64.
    Durie F, Aruffo A, Ledbetter J, et al. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J Clin Invest 1994; 94: 1333–8PubMedCrossRefGoogle Scholar
  65. 65.
    Lu L, Li W, Fu F, et al. Blockade of the CD40-CD40 ligand pathway potentiates the capacity of donor-derived dendritic cell progenitors to induce long term cardiac allogaft survival. Transplantation 1997; 64: 1808–15PubMedCrossRefGoogle Scholar
  66. 66.
    Markees T, Appel M, Noelle R, et al. Tolerance to islet xenograft induced by dual manipulation of antigen presentation and co-stimulation. Transplant Proc 1996; 28(2): 814–5PubMedGoogle Scholar
  67. 67.
    Markees T, Phillips N, Noelle R, et al. Prolonged survival of mouse skin allografts in recipients treated with donor splenocytes and antibody to CD40 ligand. Transplantation 1997; 64: 329–35PubMedCrossRefGoogle Scholar
  68. 68.
    Markees T, Phillips N, Gordon E, et al. Long-term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomized mice requires CD4+ T cells, interferon-γ and CTLA4. J Clin Invest 1998; 101(11): 2446–55PubMedCrossRefGoogle Scholar
  69. 69.
    Markees T, Phillips N, Gordon E, et al. Prolonged skin allograft survival in mice treated with Flt3-ligand induced dendritic cells and anti-CD 154 monoclonal antibody. Transplant Proc 1999; 31: 884–5PubMedCrossRefGoogle Scholar
  70. 70.
    Nathan M, Li K, Bishop D. CD40-CD40 ligand interactions during allograft rejection: CD40L blockade versus the use of CD40 deficient recipients [abstract no. 37]. The Sixth Basic Science Symposium of the Transplantation Society; 1999 Aug 25–29; Monterey (CA): 55Google Scholar
  71. 71.
    Sun H, Subbotin V, Chen C, et al. Prevention of chronic rejection in mouse aortic allografts by combined treatment with CTLA4Ig and anti-CD40 ligand monoclonal antibody. Transplantation 1997; 64(12): 1838–56PubMedCrossRefGoogle Scholar
  72. 72.
    Rossini A, Parker D, Phillips N, et al. Induction of immunological tolerance to islet allografts. Cell Transplantation 1996; 15(1): 49–52CrossRefGoogle Scholar
  73. 73.
    Rossini A, Mordes J, Markees T, et al. Induction of islet transplantation tolerance using donor specific transfusion and anti-CD154 monoclonal antibody. Transplant Proc 1999; 31: 629–32PubMedCrossRefGoogle Scholar
  74. 74.
    Parker D, Greiner D, Phillips N, et al. Survival of mouse pancreatic islet allografts in recipients treated with allogenic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci USA 1995; 92: 9560–4PubMedCrossRefGoogle Scholar
  75. 75.
    Boulday G, Bremand L, Karam G, et al. Effect of the blockade of the costimulation pathway by anti-B7 antibodies in renal allotransplantation in baboons. Transplant Proc 2001; 33: 241–2PubMedCrossRefGoogle Scholar
  76. 76.
    Chang A, Blum M, Blair K, et al. Prolonged anti-CD40 ligand therapy improves primate allograft cardiac survival. Transplant Proc 1999; 31: 95PubMedCrossRefGoogle Scholar
  77. 77.
    Elster E, Xu H, Tadaki DK, et al. Primate skin allotransplantation with anti-CD154 monotherapy. Transplant Proc 2001; 33: 675–6PubMedCrossRefGoogle Scholar
  78. 78.
    Hausen B, Klupp J, Hook L, et al. Pretransplant administration of humanised monoclonals against B7.1 and B7.2 epitopes improve graft outcome after life supporting renal transplantation in primates [abstract no. 0087]. XVIII International Congress of the Transplantation Society; 2000; Rome: 22Google Scholar
  79. 79.
    Kenyon N, Chatzipetrous M, Masetti M, et al. Long-term survival and function of intrahepatic islet allografts in rhesus monkey s treated with humanised anti-CD 154. Proc Natl Acad Sci USA 1999; 96: 8132–7PubMedCrossRefGoogle Scholar
  80. 80.
    Pierson R, Chang A, Blum M, et al. Prolongation of primate cardiac allograft survival by treatment with anti-CD40-ligand (CD154) antibody. Transplantation 1999; 68: 1800–22PubMedCrossRefGoogle Scholar
  81. 81.
    Lehmann R, Kenyon N, Fernandez L, et al. Prevention of rejection allows for maintenance of islet cell mass at prepancreatectomy levels in baboon (papio hamadryas) recipients of islet allografts. Diabetes 1998; 47(Suppl. 1): A75Google Scholar
  82. 82.
    Levisetti M, Padrid P, Szot GL, et al. Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogenic pancreatic islet transplantation. J Immunol 1997; 159: 5187–91PubMedGoogle Scholar
  83. 83.
    Kirk A. Allotransplantation without immunosuppression: the development of tolerance strategies for human transplantation. International Speakers’ Abstracts. The Transplant Society of Australia & New Zealand 18th Annual Scientific Meeting; 2000 Apr 12–14; Canberra, ACT, AustraliaGoogle Scholar
  84. 84.
    Li Y, Li X, Zheng X, et al. Blocking both signal 1 and 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999; 5(11): 1298–302PubMedCrossRefGoogle Scholar
  85. 85.
    Smiley S, Csizmadia V, Gao W, et al. Differential effects of cyclosporine A, methylprednisolone, mycophenolate and rapamycin on CD154 induction and requiremnent for NFkB. Transplantation 2000; 70(3): 415–9PubMedCrossRefGoogle Scholar
  86. 86.
    Vanhove B, Laflamme G, Coulon F, et al. Selective blockade of CD28-B7 interaction, but not of CTLA4-B7, with a SCFV-alpha 1 antitrypsin fusion proteins. Am J Transplant 2001; 1(1):S144Google Scholar
  87. 87.
    Linsley P, Wallace P, Johnson J, et al. Immunosuppression in vivo by a soluble form of the CTLA4 T cell activation molecule. Science 1992; 257: 792–5PubMedCrossRefGoogle Scholar
  88. 88.
    Ross S, Delrivere L, Gibbs P, et al. Adenovirus mediated delivery of CTLA4-Ig can induce tolerance but results in severe graft damage [abstract no. 41]. The Sixth Basic Sciences Symposium of the Transplantation Society; 1999 Aug 25–29; Monterey (CA): 59Google Scholar
  89. 89.
    Pearson T, Alexander D, Winn K, et al. Transplantation tolerance induced by CTLA4-Ig. Transplantation 1994; 57: 1701–6PubMedGoogle Scholar
  90. 90.
    Pearson T, Alexander D, Hendrix R, et al. CTLA4-Ig plus bone marrow induces long term allograft survival and donor-specific unresponsiveness in the murine model. Transplantation 1996; 61: 997–1004PubMedCrossRefGoogle Scholar
  91. 91.
    Guinan E, Boussiotis V, Neuberg D, et al. Transplantation of anergic histocompatible bone marrow allografts. N Engl J Med 1999; 340: 1704–4PubMedCrossRefGoogle Scholar
  92. 92.
    Russell M, Hancock W, Akalin E, et al. Chronic cardiac rejection in the LEW to F344 rat model. J Clin Invest 1996; 97(3): 833–8PubMedCrossRefGoogle Scholar
  93. 93.
    Lin H, Boiling S, Linsley P, et al. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med 1993; 178: 1801–6PubMedCrossRefGoogle Scholar
  94. 94.
    Turka L, Linsley P, Lin H, et al. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci USA 1992; 89: 11102–5PubMedCrossRefGoogle Scholar
  95. 95.
    Yin D, Fathman G. Induction of tolerance to heart allografts in high responder rats by combining anti-CD4 with CTLA4Ig. J Immunol 1995; 155: 1655–9PubMedGoogle Scholar
  96. 96.
    Perico N, Amuchastegui S, Bontempelli M, et al. CTLA4Ig alone or in combination with low dose cyclosporine fails to reverse acute rejection of renal allograft in the rat. Transplantation 1996; 61: 1320–2PubMedCrossRefGoogle Scholar
  97. 97.
    Sayegh M, Akalin E, Hancoc W, et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 1995; 181: 1869–74PubMedCrossRefGoogle Scholar
  98. 98.
    Lenschow D, Zeng Y, Thistlethwaite R, et al. Long-term survival of xenogenic pancreatic islet grafts induced by CTLA4Ig. Science 1992; 257: 789–92PubMedCrossRefGoogle Scholar
  99. 99.
    Olthoff K, Judge T, Gelman A, et al. Adenovirus-mediated gene transfer into cold-preserved liver allografts: survival pattern and unresponsiveness following transduction with CTLA4Ig. Nat Med 1998; 4(2): 194–200PubMedCrossRefGoogle Scholar
  100. 100.
    Sayegh M, Zheng X, Magee C, et al. Donor antigen is necessary for the prevention of chronic rejection in CTLA4Ig treated murine cardiac allograft recipients. Transplantation 1997; 64: 1646–50PubMedCrossRefGoogle Scholar
  101. 101.
    Azuma H, Chandraker A, Nadeau K, et al. Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection. Proc Natl Acad Sci USA 1996; 93: 12439–44PubMedCrossRefGoogle Scholar
  102. 102.
    Bluestone J. Costimulation and its role in organ transplantation. Clin Transplant 1996; 10: 104–9PubMedGoogle Scholar
  103. 103.
    Ossevoort M, Boer MD, Lorre K, et al. Blocking of the costimulatory pathways using monoclonal antibodies as a new strategy to prevent transplant rejection in a non-human primate model. Transplant Proc 1998; 30: 1061–2PubMedCrossRefGoogle Scholar
  104. 104.
    Guinan E, Gribben J, Boussiotis V, et al. Pivotal role of the B7: CD28 pathway in transplantation tolerance and tumor immunity. Blood 1994; 84(10): 3261–82PubMedGoogle Scholar
  105. 105.
    Vincent J. Biogen says it has stopped ongoing trials of Anti-CD40 ligand monoclonal antibody [online]. Available from URL: Accessed 1999 Nov 2]
  106. 106.
    Kawai T, Andrews D, Colvin R, et al. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand [letter]. Nat Med 2000; 6: 114Google Scholar
  107. 107.
    Kirk A, Harlan D. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand — reply [letter]. Nat Med 2000; 6: 114Google Scholar
  108. 108.
    Henn V, Slupsky J, Grafe M, et al. CD40 ligand on activated platelets an inflammatory reaction of endothelial cells. Nature 1998; 391: 591–4PubMedCrossRefGoogle Scholar
  109. 109.
    Abrams J, Lebwohl M, Guzzo C, et al. CTLA4-Ig mediated blockade of T-cell costimulation in patients with psoriasis vulgaris. J Clin Invest 1999; 103(9): 1243–52PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.The New Zealand Liver Transplant UnitAuckland District Health BoardAucklandNew Zealand

Personalised recommendations