Donor-Specific Tolerance

  • Au H. Bui
  • Gerald Lipshutz
  • Jerzy Kupiec-Weglinski

The widespread use of immunosuppressive drugs within the last several decades has without doubt contributed to the effectiveness and overall success of solid organ transplantation. In 1965, the first immune suppressive drugs consisted of treatment with azathioprine and corticosteroids. Since then, more efficacious drugs (e.g., calcineurin inhibitors, mycophenolate mofetil, rapamycin, monoclonal antibodies against CD3, and CD25) have emerged such that the problems associated with acute rejection have been mainly overcome. Chronic rejection though still remains a serious problem and limitation to organ transplantation. In fact, only 50% of kidney transplants that survive the first 12 months are still functioning 7.5–9.5 years later. Long-term immune suppression has not provided the benefits observed in short-term graft survival.


Graft Survival Solid Organ Transplantation Costimulatory Molecule Transplantation Tolerance Treg Population 
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  1. 1.
    R. Y. Calne, B. A. Hurn, Combined immunosuppressive action of phytohaemagglutinin and azathioprine (Imuran) on dogs with renal homotransplants, Br Med J 5454, 154–155 (1965).CrossRefGoogle Scholar
  2. 2.
    J. Cecka, Clinical Transplants, UCLA Tissue Typing Laboratory, pp. 1–14 (1996).Google Scholar
  3. 3.
    J. M. Dubernard, G. Herzberg, et al., Human hand allograft: report on first 6 months, Lancet 353, 1315 (1999).PubMedCrossRefGoogle Scholar
  4. 4.
    J. W. Jones, J. H. Barker, W. C. Breidenbach, Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team, N Engl J Med 343, 468 (2000).PubMedCrossRefGoogle Scholar
  5. 5.
    C. G. Francois, C. Maldonado, et al., Hand transplantation: comparisons and observations of the first four clinical cases, Microsurgery 20, 360 (2000).PubMedCrossRefGoogle Scholar
  6. 6.
    A. Kirk, Induction Immunosuppression, Transplantation 82, 593–602 (2006).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Pascual, T. Kawai, N. Tolkoff-Rubin, A. B. Cosimi, Strategies to improve long-term outcomes after renal transplantation, N Engl J Med 346(8), 580–590 (2002).PubMedCrossRefGoogle Scholar
  8. 8.
    M. Lanzetta, R. Margreiter, et al., The international registry on hand and composite tissue transplantation, Transplantation 79, 1210 (2005).PubMedCrossRefGoogle Scholar
  9. 9.
    A. D. Kirk, D. S. Batty, R. E. Baumgartner, J. D. Berning, K. Buchanan, Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates, Nat Med 5(6), 686–693 (1999).PubMedCrossRefGoogle Scholar
  10. 10.
    R. Germain, The art of the probable: system control in the adaptive immune system, Science 293, 240 (2001).PubMedCrossRefGoogle Scholar
  11. 11.
    P. Matzinger, The danger model: a renewed sense of self, Science 296, 301 (2002).PubMedCrossRefGoogle Scholar
  12. 12.
    M. H. Sayegh, C. B. Carpenter, Mechanisms of T cell recognition of alloantigen: the role of peptides, Transplantation 57, 1295–1302 (1994).PubMedCrossRefGoogle Scholar
  13. 13.
    R. I. Ciubotariu, J. R. Batchelor, et al., Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts, J Clin Invest 101, 398–405 (1998).PubMedCrossRefGoogle Scholar
  14. 14.
    Nikolic B, Skyes M. Mixed hematopoietic chimerism and transplantation tolerance, Immunol Res 16(3), 217–228 (1997).PubMedCrossRefGoogle Scholar
  15. 15.
    J. O. Manilay, K. G. Swenson, M. Sykes, Intrathymic deletion of alloreative T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regiment, Transplantation 66(1), 96–102 (1998).PubMedCrossRefGoogle Scholar
  16. 16.
    X. C. Li, T. B. Strom, L. A. Turka, A. D. Wells, T cell death and transplantation tolerance, Immunity 14, 407–416 (2001).PubMedCrossRefGoogle Scholar
  17. 17.
    H. Jonuleit, E. Schmitt, The regulatory T cell family: distinct subsets and their interrelations, J Immunol 171, 6323–6327 (2003).PubMedGoogle Scholar
  18. 18.
    S. Sakaguchi, M. Asano, et al., Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD 25). Breakdown of a single meechanism of self tolerance causes varius autoimmune diseases, J. Immunol 155, 1151–1164 (1995).PubMedGoogle Scholar
  19. 19.
    C. Baecher-Allan, G. Freeman, et al., CD4+Cd25+ high regulatory cells in human peripheral blood, J Immunol 167, 1245 (2001).PubMedGoogle Scholar
  20. 20.
    M. Gilliet, Generation of human Cd8 T regulatory cells by CD40 ligand-activated plasmacytoide dendritic cells, J Exp Med 195, 695–704 (2002).PubMedCrossRefGoogle Scholar
  21. 21.
    K. J. Wood, Regulatory T cells in transplantation tolerance, Nat Rev Immunol 3, 199–210 (2003).PubMedCrossRefGoogle Scholar
  22. 22.
    S. Hori, S. Sakaguchi, Control of regulatory T cell development by the transcription factor Foxp3, Science 299, 1057–1061 (2003).PubMedCrossRefGoogle Scholar
  23. 23.
    Y. Chen, V. K. Kuchroo, J. Inobe, et al., Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis, Science 265, 1237–1240 (1994).PubMedCrossRefGoogle Scholar
  24. 24.
    H. Groux, et al., A CD4+ T cell subset inhibits antigen specific T cell responses and prevents colitis, Nature 389, 737–742 (1997).PubMedCrossRefGoogle Scholar
  25. 25.
    M. Stassen, E. Schmitt, H. Jonuleit, Human CD(4+) CD(25+) regulatory T cells and infectious tolerance, Transplantation 77 (1 Suppl), S23–S25 (2004).PubMedCrossRefGoogle Scholar
  26. 26.
    H. Waldmann, S. Cobbold, Regulating the immune response to transplants: a role for CD4+ regulatory cells? Immunity 14, 399–406 (2001).PubMedCrossRefGoogle Scholar
  27. 27.
    H. Jonuleit, E. Schmitt, G. Schuler, J. Knop, A. H. Enk, Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells, J Exp Med 192, 1213–1222 (1992).CrossRefGoogle Scholar
  28. 28.
    X. X. Zheng, et al., Favorably tipping the balance between cytopathic and regulatory T cells to create transplantation tolerance, Immunity 19, 503–514 (2003).PubMedCrossRefGoogle Scholar
  29. 29.
    D. M. Rothstein, et al., T cell costimulatory pathways in allograft rejection and tolerance, Immunol Rev 196, 85 (2003).PubMedCrossRefGoogle Scholar
  30. 30.
    R. Schwartz, A cell culture model for T lymphocyte clonal anergy, Science 248(4961), 1349 (1990).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Takada, K. C. Nadeau, et al., The role of the B7 costimulatory pathway in experimental cold ischemia/reperfusion injury, J Clin Invest 100, 1199 (1997).PubMedCrossRefGoogle Scholar
  32. 32.
    M. K. Jenkins, S. D. Norton, K. B. Urdahl, CD28 delivers a costimulatory signal involved in antigen specific IL-2 production by human T cells, J Immunol 147(8), 2461 (1991).PubMedGoogle Scholar
  33. 33.
    P. S. Linsley, J. Johnson, et al., Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule, Science 257, 789–792 (1992).PubMedCrossRefGoogle Scholar
  34. 34.
    R. I. Lechler, L. A. Turka, The complementary roles of deletion and regulation in transplantation tolerance, Nat Rev Immunol 3(2), 147–158 (2003).PubMedCrossRefGoogle Scholar
  35. 35.
    Y. Ishida, K. Shibahara, T. Honjo, Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death, EMBO J 11, 3887–3895 (1992).PubMedGoogle Scholar
  36. 36.
    H. Nishimura H, et al., Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor, Immunity 11, 141–151 (1992).CrossRefGoogle Scholar
  37. 37.
    G. J. Freeman, R. Ahmed, A. H. Sharpe, Reinvigorating exhausted HIV-specific T cells via PD-1PD-1 ligand blockade, J Exp Med 203(10), 2223–2227 (2006).PubMedCrossRefGoogle Scholar
  38. 38.
    A. D. Kirk, N. N. Armstrong, et al., CTLA4Ig and anti-CD40 ligand prevent renal allograft rejection in primates, Proc Natl Acad Sci USA 94, 8789 (1997).PubMedCrossRefGoogle Scholar
  39. 39.
    A. D. Kirk, H. Sollinger, et al., Preliminary results of the use of humanized anti-CD154 in human renal allotransplantation, Am J Transplant 1, S191 (2001).Google Scholar
  40. 40.
    A. D. Kirk, A. Celniker, et al., Induction therapy with monoclonal antibodies specific for CD80 and CD86 delays the onset of acute renal allograft rejection in non-human primates, Transplantation 72, 377 (2001).PubMedCrossRefGoogle Scholar
  41. 41.
    C. P. Larsen, A. B. Adams, et al., Rational development of LEA29Y (belatacept), a high affinity variant of CTLA4-Ig with potent immunosuppressive properties, Am J Transplant 5, 443 (2005).PubMedCrossRefGoogle Scholar
  42. 42.
    F. Vincenti, A. Durrbach, et al., Costimulation Blockade with belatacept in renal transplantation, N Engl J Med 353, 770–781 (2005).PubMedCrossRefGoogle Scholar
  43. 43.
    Y. Sharabi, D.H. Sachs, Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen, J Exp Med 169(2), 493–502 (1989).PubMedCrossRefGoogle Scholar
  44. 44.
    E. L. Lagaaij, et al., Effect of one-HLA-DR-antigen-matched and completely HLA-DR-mismatched blood transfusions on survival of heart and kidney allografts, N Engl J Med 321(11), 701–705 (1989).PubMedGoogle Scholar
  45. 45.
    D. Middleton, et al., Transfusion of one HLA-DR antigen-matched blood to potential recipients of a renal allograft, Transplantation 58(7), 845–848 (1994).PubMedCrossRefGoogle Scholar
  46. 46.
    W. Wong, P. J. Morris, K. J. Wood, Syngeneic bone marrow expressing a single donor class I MHC molecule permits acceptance of a fully allogeneic cardiac allograft. Transplantation 62(10), 1462–1468 (1996).PubMedCrossRefGoogle Scholar
  47. 47.
    A. de Vries-van der Zwan, et al., Specific tolerance induction and transplantation: a single-day protocol, Blood 89(7), 2596–2601 (1997).Google Scholar
  48. 48.
    O. Salvatierra Jr., et al., Pretreatment with donor-specific blood transfusions in related recipients with high MLC, Transplant Proc 13(1 Pt 1), 142–149 (1981).PubMedGoogle Scholar
  49. 49.
    G. Opelz, B. Graver, P. I. Terasaki, Induction of high kidney graft survival rate by multiple transfusion, Lancet 1(8232), 1223–1225 (1981).PubMedCrossRefGoogle Scholar
  50. 50.
    C. B. Carpenter, Deliberate transfusion of potential renal transplant recipients with specific donor blood, Am J Kidney Dis 1(2), 116–118 (1981).PubMedGoogle Scholar
  51. 51.
    T. Leivestad, et al., Effect of pretransplant donor-specific transfusions in renal transplantation, Transplant Proc 14(2), 370–373 (1982).PubMedGoogle Scholar
  52. 52.
    C. B. Anderson, G. A. Sicard, E. E. Etheredge, Pretreatment of renal allograft recipients with azathioprine and donor-specific blood products, Surgery 92(2), 315–321 (1982).PubMedGoogle Scholar
  53. 53.
    G. Opelz, et al., Effect of blood transfusions on subsequent kidney transplants, Transplant Proc 5(1), 253–259 (1973).PubMedGoogle Scholar
  54. 54.
    N. Akiyama, et al., Effects of donor-specific blood transfusion on the survival of living related renal grafts, Jpn J Exp Med 54(5), 225–227 (1984).PubMedGoogle Scholar
  55. 55.
    W. J. Burlingham, et al., Improved renal allograft survival following donor-specific transfusions. I. Induction of antibodies that inhibit primary antidonor MLC response, Transplantation 39(1), 12–17 (1985).PubMedGoogle Scholar
  56. 56.
    W. W. Pfaff, et al., Planned random donor blood transfusion in preparation for transplantation. Sensitization and graft survival, Transplantation 38(6), 701–703 (1984).PubMedCrossRefGoogle Scholar
  57. 57.
    G. Opelz, P. I. Terasaki, Improvement of kidney-graft survival with increased numbers of blood transfusions, N Engl J Med 299(15), 799–803 (1978).PubMedGoogle Scholar
  58. 58.
    D. Potter, et al., Effect of donor-specific transfusions on renal transplantation in children, Pediatrics 76(3), 402–405 (1985).PubMedGoogle Scholar
  59. 59.
    L. Yang, et al., Mechanisms of long-term donor-specific allograft survival induced by pretransplant infusion of lymphocytes, Blood 91(1), 324–330 (1998).PubMedGoogle Scholar
  60. 60.
    D. C. Brennan, T. Mohanakumar, M. W. Flye, Donor-specific transfusion and donor bone marrow infusion in renal transplantation tolerance: a review of efficacy and mechanisms, Am J Kidney Dis 26(5), 701–715 (1995).PubMedCrossRefGoogle Scholar
  61. 61.
    W. H. Barber, Donor-specific transfusions in renal transplantation, Clin Transplant 8(2 Pt 2), 204–206 (1994).PubMedGoogle Scholar
  62. 62.
    M. Otsuka, et al., Long-term graft survival of living-related kidneys after donor-specific transfusion, Transplant Proc 32(7), 1741–1742 (2000).PubMedCrossRefGoogle Scholar
  63. 63.
    E. van Twuyver, et al., Pretransplantation blood transfusion revisited, N Engl J Med 325(17), 1210–1213 (1991).PubMedCrossRefGoogle Scholar
  64. 64.
    E. van Twuyver, et al., High-affinity cytotoxic T lymphocytes after non-HLA-sharing blood transfusion-the other side of the coin, Transplantation 57(8), 1246–1251 (1994).PubMedCrossRefGoogle Scholar
  65. 65.
    O. Salvatierra Jr., et al., Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach, Ann Surg 192(4), 543–552 (1980).PubMedCrossRefGoogle Scholar
  66. 66.
    B. W. Colombe, et al., Two patterns of sensitization demonstrated by recipients of donor-specific transfusion. Limitations to control by Imuran, Transplantation 44(4), 509–515 (1987).PubMedCrossRefGoogle Scholar
  67. 67.
    C. B. Anderson, et al., Pretreatment of renal allograft recipients with immunosuppression and donor-specific blood, Transplantation 38(6), 664–668 (1984).PubMedCrossRefGoogle Scholar
  68. 68.
    R. M. Radvany, K.M. Patel, Donor-specific transfusions. Donor-recipient HLA compatibility, recipient HLA haplotype, and antibody production, Transfusion 28(2), 137–141 (1988).PubMedCrossRefGoogle Scholar
  69. 69.
    J. S. Cheigh, et al., Minimal sensitization and excellent renal allograft outcome following donor-specific blood transfusion with a short course of cyclosporine, Transplantation 51(2), 378–381 (1991).PubMedCrossRefGoogle Scholar
  70. 70.
    D. E. Potter, et al., Are blood transfusions beneficial in the cyclosporine era? Pediatr Nephrol 5(1), 168–172 (1991).PubMedCrossRefGoogle Scholar
  71. 71.
    K. J. Wood, J. Fry, Gene therapy: potential applications in clinical transplantation. Expert Rev Mol Med 1999, 1–20 (1999).Google Scholar
  72. 72.
    D. J. Moore, J. F. Markmann, S. Deng, Avenues for immunomodulation and graft protection by gene therapy in transplantation, Transpl Int 19(6), 435–445 (2006).PubMedCrossRefGoogle Scholar
  73. 73.
    W. W. Hancock, Chemokine receptor-dependent alloresponses, Immunol Rev 196, 37–50 (2003).PubMedCrossRefGoogle Scholar
  74. 74.
    R. Horuk, et al., A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection, J Biol Chem 276(6), 4199–4204 (2001).PubMedCrossRefGoogle Scholar
  75. 75.
    W. Gao, et al., Targeting of the chemokine receptor CCR1 suppresses development of acute and chronic cardiac allograft rejection, J Clin Invest 105(1), 35–44 (2000).PubMedCrossRefGoogle Scholar
  76. 76.
    W. Gao, et al., Beneficial effects of targeting CCR5 in allograft recipients, Transplantation 72(7), 1199–1205 (2001).PubMedCrossRefGoogle Scholar
  77. 77.
    J. H. Gong, et al., RANTES and MCP-3 antagonists bind multiple chemokine receptors, J Biol Chem 271(18), 10521–10527 (1996).PubMedCrossRefGoogle Scholar
  78. 78.
    G. Vassalli, et al., Lentiviral gene transfer of the chemokine antagonist RANTES 9–68 prolongs heart graft survival, Transplantation 81(2), 240–246 (2006).PubMedCrossRefGoogle Scholar
  79. 79.
    D. Forman, C. Tian, J. Iacomini, Induction of donor-specific tolerance in sublethally irradiated recipients by gene therapy, Mol Ther 12(2), 353–359 (2005).PubMedCrossRefGoogle Scholar
  80. 80.
    N. Emmanouilidis, C. P. Larsen, Induction of chimerism and tolerance using freshly purified or cultured hematopoietic stem cells in nonmyeloablated mice, Methods Mol Med 109, 459–468 (2005).PubMedGoogle Scholar
  81. 81.
    H. Hayashi, et al., Role of the thymus in donor specific hyporesponsiveness induced by retroviral transduction of bone marrow using an MHC class I gene, Transplant Proc 29(1–2), 1133 (1997).PubMedCrossRefGoogle Scholar
  82. 82.
    J. Bagley, et al., Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy, Blood 99(12), 4394–4399 (2002).PubMedCrossRefGoogle Scholar
  83. 83.
    J. Bagley, J. Iacomini, Gene therapy progress and prospects: gene therapy in organ transplantation, Gene Ther 10(8), 605–611 (2003).PubMedCrossRefGoogle Scholar
  84. 84.
    R. S. Mayfield, et al., The mechanism of specific prolongation of class I-mismatched skin grafts induced by retroviral gene therapy, Eur J Immunol 27(5), 1177–1181 (1997).PubMedCrossRefGoogle Scholar
  85. 85.
    R. de Waal Malefyt, et al., Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes, J Exp Med 174(5), 1209–1220 (1991).PubMedCrossRefGoogle Scholar
  86. 86.
    P. Ralph, et al., IL-10, T lymphocyte inhibitor of human blood cell production of IL-1 and tumor necrosis factor, J Immunol 148(3), 808–814 (1992).PubMedGoogle Scholar
  87. 87.
    L. A. DeBruyne, et al., Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses, Gene Ther 5(8), 1079–1087 (1998).PubMedCrossRefGoogle Scholar
  88. 88.
    M. S. Lee, et al., Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction, J Clin Invest 93(3), 1332–1338 (1994).PubMedCrossRefGoogle Scholar
  89. 89.
    N. Yanagida, et al., Tolerance induction by a single donor pretreatment with the adenovirus vector encoding CTLA4Ig gene in rat orthotopic liver transplantation, Transplant Proc 33(1–2), 573–574 (2001).PubMedCrossRefGoogle Scholar
  90. 90.
    M. Nomura, et al., Induction of donor-specific tolerance by adenovirus-mediated CD40Ig gene therapy in rat liver transplantation, Transplantation 73(9), 1403–1410 (2002).PubMedCrossRefGoogle Scholar
  91. 91.
    K. Yamashita, et al., Long-term acceptance of rat cardiac allografts on the basis of adenovirus mediated CD40Ig plus CTLA4Ig gene therapies, Transplantation 76(7), 1089–1096 (2003).PubMedCrossRefGoogle Scholar
  92. 92.
    L. J. West, K. Tao, Acceptance of third-party cardiac but not skin allografts induced by neonatal exposure to semi-allogeneic lymphohematopoietic cells, Am J Transplant 2(8), 733–744 (2002).PubMedCrossRefGoogle Scholar
  93. 93.
    A. C. Nathwani, A.M. Davidoff, D.C. Linch, A review of gene therapy for haematological disorders, Br J Haematol 128(1), 3–17 (2005).PubMedCrossRefGoogle Scholar
  94. 94.
    A. B. Adams, C. P. Larsen, Heterologous immunity: an overlooked barrier to tolerance, Immunol Rev 196, 147–160 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Au H. Bui
    • 1
  • Gerald Lipshutz
    • 2
  • Jerzy Kupiec-Weglinski
    • 3
  1. 1.Division of Transplantation, Department of SurgeryDavid Geffen School of Medicine at UCLALos Angeles
  2. 2.Departments of Surgery and Urology, UCLA Medical CenterDavid Geffen School of Medicine at UCLALos Angeles
  3. 3.Division of Liver and Pancreas Transplantation, Department of SurgeryDavid Geffen School of Medicine at UCLALos Angeles

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