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Immune Tolerance Induction: Basic Concepts for Composite Tissue Allotransplantation

  • Patricio Andrades
  • Clement Asiedu
  • Judith M. Thomas

Despite remarkable progress in contemporary transplantation there are still major unresolved problems in the field. First, although immunosuppressive drugs have dramatically improved the life of transplant recipients over the past 30 years, they are associated with significant toxicities. This includes both the toxicities of immunosuppression itself (enhanced risk of opportunistic infections and selected malignancies), and side effects unrelated to immunosuppression (nephrotoxicity of calcineurin inhibitors, hypertension and cardiovascular disease from corticosteroids, etc.). Second, these agents have proven very successful in the prevention and treatment of acute rejection, but similar success has not been achieved in preventing chronic rejection and extending graft survival for decades. Even though various promising new agents are currently being developed and investigated, the undeniable conclusion is that chronic immunosuppressive drug therapy in its present status is not a satisfactory solution to the unremitting problem of host alloaggressiveness. This is a major obstacle to widespread application of composite tissue transplantation that can potentially be eliminated by induction of transplantation tolerance.

Keywords

Tolerance Induction Donor Bone Marrow Curr Opin Immunol Transplantation Tolerance Costimulatory Pathway 
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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References

  1. 1.
    R. I. Lechler, M. Sykes, A. W. Thomson, L. A. Turka, Organ transplantation-how much of the promise has been realized? Nat Med 11(6), 605–613 (2005).PubMedCrossRefGoogle Scholar
  2. 2.
    P. B. Medawar, The behavior and fate of skin autografts and skin homografts in rabbits, J Anat 78, 176–178 (1944).PubMedGoogle Scholar
  3. 3.
    R. D. Owen, Immunogenetic consequences of vascular anastomoses between bovine twins, Science 102, 400–401 (1945).PubMedCrossRefGoogle Scholar
  4. 4.
    R. E. Billingham, L. Brent, P. B. Medawar, Actively acquired tolerance of foreign cells, Nature 172, 603–606 (1953).PubMedCrossRefGoogle Scholar
  5. 5.
    J. M. Thomas, K. M. Verbanac, Transplant tolerance induction: basic concepts and therapeutic approaches, Lieberman R, Mukherjee A, editors. New York: R. G. Landes Compony; 1996.Google Scholar
  6. 6.
    A. P. Monaco, P. J. Morris, Clinical tolerance: the end of the beginning, Transplantation 77(6), 921–925 (2004).PubMedCrossRefGoogle Scholar
  7. 7.
    R. Y. Calne, Prope tolerance – the future of organ transplantation from the laboratory to the clinic, Int Immunopharmacol 5(1), 163–167 (2005).PubMedCrossRefGoogle Scholar
  8. 8.
    A. P. Monaco, Prospects and strategies for clinical tolerance, Transplant Proc 36(1), 227–231 (2004).PubMedCrossRefGoogle Scholar
  9. 9.
    D. H. Sachs, Tolerance: of mice and men, J Clin Invest 111(12), 1819–1821 (2003).PubMedGoogle Scholar
  10. 10.
    L. A. Turka, What’s new in transplant immunology: problems and prospects, Ann Intern Med 128(11), 946–948 (1998).PubMedGoogle Scholar
  11. 11.
    S. H. Adler, L. A. Turka, Immunotherapy as a means to induce transplantation tolerance, Curr Opin Immunol 14(5), 660–665 (2002).PubMedCrossRefGoogle Scholar
  12. 12.
    F. G. Lakkis, A. Arakelov, B. T. Konieczny, Y. Inoue, Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue, Nat Med 6(6), 686–688 (2002).CrossRefGoogle Scholar
  13. 13.
    F. M. Burnet, The clonal selection theory of acquired immunity, New York: Cambridge University Press; 1959.Google Scholar
  14. 14.
    M. Sykes, D. H. Sachs, Bone marrow transplantation as a means of inducing tolerance, Semin Immunol 2(6), 401–417 (1990).PubMedGoogle Scholar
  15. 15.
    J. Miller, J. M. Mathew, V. Esquenazi, Toward tolerance to human organ transplants: a few additional corollaries and questions, Transplantation 77(6), 940–942 (2004).PubMedCrossRefGoogle Scholar
  16. 16.
    A. L. Lobashevsky, X. L. Jiang, J. M. Thomas, Allele-specific in situ analysis of microchimerism by fluorescence resonance energy transfer (FRET) in nonhuman primate tissues, Hum Immunol 63(2), 108–120 (2002).PubMedCrossRefGoogle Scholar
  17. 17.
    S. Strober, R. J. Lowsky, J. A. Shizuru, J. D. Scandling, M. T. Millan, Approaches to transplantation tolerance in humans, Transplantation 77(6), 932–936 (2004).PubMedCrossRefGoogle Scholar
  18. 18.
    A. S. Rao, T. E. Starzl, A. J. Demetris, M. Trucco, A. Thomson, S. Qian, N. Murase, J. J. Fung, The two-way paradigm of transplantation immunology, Clin Immunol Immunopathol 80(3 Pt 2), S46–S51 (1996).PubMedCrossRefGoogle Scholar
  19. 19.
    W. J. Hubbard, J. M. Thomas, Cytoablation and cytoreduction strategies in transplant tolerance, Curr Opin Immunol 2, 36–46 (1997).Google Scholar
  20. 20.
    R. D. Moses, J. T. Sundeen, K. S. Orr, R. R. Roberts, R. E. Gress, Cardiac allograft survival across major histocompatibility complex barriers in the rhesus monkey following T lymphocyte-depleted autologous marrow transplantation. III. Late allograft rejection, Transplantation 48(5), 769–773 (1989).PubMedCrossRefGoogle Scholar
  21. 21.
    R. I. Lechler, M. Sykes, A. W. Thomson, L. A. Turka, Organ transplantation – how much of the promise has been realized? Nat Med 11(6), 605–613 (2005).PubMedCrossRefGoogle Scholar
  22. 22.
    J. M. Thomas, J. L. Contreras, C. A. Smyth, A. Lobashevsky, S. Jenkins, W. J. Hubbard, D. E. Eckhoff, S. Stavrou, D. M. Neville Jr., F. T. Thomas, Successful reversal of streptozotocin-induced diabetes with stable allogeneic islet function in a preclinical model of type 1 diabetes, Diabetes 50(6), 1227–1236 (2001).PubMedCrossRefGoogle Scholar
  23. 23.
    G. Meng, Y. Jiang, W. Hubbard, J. M. Thomas, The effect of anti-CD3-immunotoxin on T lymphocyte function in vitro, Transpl Immunol 6(1), 53–59 (1998).PubMedCrossRefGoogle Scholar
  24. 24.
    W. J. Hubbard, J. L. Contreras, D. E. Eckhoff, F. T. Thomas, J. M. Thomas, Immunotoxins and tolerance induction in primates, Curr Opin Immunol 5, 29–34 (2000).Google Scholar
  25. 25.
    A. Hutchings, J. M. Thomas, Transplantation: tolerance, Curr Opin Investig Drugs 4(5), 530–535 (2003).PubMedGoogle Scholar
  26. 26.
    T. E. Starzl, N. Murase, K. Abu-Elmagd, E. A. Gray, R., et al, Tolerogenic immunosuppression for organ transplantation, Lancet 361(9368), 1502–1510 (2003).PubMedCrossRefGoogle Scholar
  27. 27.
    H. Gudmundsdottir, L. A. Turka, T cell costimulatory blockade: new therapies for transplant rejection, J Am Soc Nephrol 10(6), 1356–1365 (1999).PubMedGoogle Scholar
  28. 28.
    Y. Li, X. C. Li, X. X. Zheng, A. D. Wells, L. A. Turka, T. B. Strom, Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance, Nat Med 5(11), 1298–1302 (1999).PubMedCrossRefGoogle Scholar
  29. 29.
    Z. Dai, B. T. Konieczny, F. K. Baddoura, F. G. Lakkis, Impaired alloantigen-mediated T cell apoptosis and failure to induce long-term allograft survival in IL-2-deficient mice, J Immunol 161(4), 1659–1663 (1998).PubMedGoogle Scholar
  30. 30.
    H. Lin, S. F. Bolling, P. S. Linsley, R. Q. Wei, D. Gordon, C. B. Thompson, L. A. Turka, Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion, J Exp Med 178(5), 1801–1806 (1993).PubMedCrossRefGoogle Scholar
  31. 31.
    C. P. Larsen, D. Z. Alexander, D. Hollenbaugh, E. T. Elwood, S. C. Ritchie, A. Aruffo, R. Hendrix, T. C. Pearson, CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway, Transplantation 61(1), 4–9 (1996).PubMedCrossRefGoogle Scholar
  32. 32.
    S. P. Montgomery, H. Xu, D. K. Tadaki, A. Celniker, L. C. Burkly, J. D. Berning, F. Cruzata, E. A. Elster, G. Gray, R. L. Kampen, S. J. Swanson, D. M. Harlan, A. D. Kirk, Combination induction therapy with monoclonal antibodies specific for CD80, CD86, and CD154 in nonhuman primate renal transplantation, Transplantation 74(10), 1365–1369 (2002).PubMedCrossRefGoogle Scholar
  33. 33.
    B. D. Elzey, J. Tian, R. J. Jensen, A. K. Swanson, J. R. Lees, S. R. Lentz, C. S. Stein, B. Nieswandt, Y. Wang, B. L. Davidson, T. L. Ratliff, Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments, Immunity 19(1), 9–19 (2003).PubMedCrossRefGoogle Scholar
  34. 34.
    J. R. Abrams, M. G. Lebwohl, C. A. Guzzo, B. V. Jegasothy, M. T. Golddfarb, et al., CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris, J Clin Invest 103(9), 1243–1252 (1999).PubMedCrossRefGoogle Scholar
  35. 35.
    J. M. Kremer, R. Westhovens, M. Leon, E. Di Giorgio, R. Alten, S. Steinfeld, et al., Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig, N Engl J Med 349(20), 1907–1915 (2003).PubMedCrossRefGoogle Scholar
  36. 36.
    C. P. Larsen, T. C. Pearson, A. B. Adams, P. Tso, N. Shirasugi, E. Strobertm, et al., Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties, Am J Transplant 5(3), 443–453 (2005).PubMedCrossRefGoogle Scholar
  37. 37.
    D. M. Rothstein, M. H. Sayegh, T-cell costimulatory pathways in allograft rejection and tolerance, Immunol Rev 196, 85–108 (2003).PubMedCrossRefGoogle Scholar
  38. 38.
    E. Ozkaynak, L. Wang, A. Goodearl, K. McDonald, S. Qin, et al., Programmed death-1 targeting can promote allograft survival, J Immunol 169(11), 6546–6553 (2002).PubMedGoogle Scholar
  39. 39.
    S. Sakaguchi, Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses, Annu Rev Immunol 22, 531–562 (2004).PubMedCrossRefGoogle Scholar
  40. 40.
    Q. Tang, K. J. Henriksen, M. Bi, E. B. Finger, G. Szot, et al., In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes, J Exp Med 199(11), 1455–1465 (2004).PubMedCrossRefGoogle Scholar
  41. 41.
    X. X. Zheng, A. Sanchez-Fueyo, C. Domenig, T. B. Strom, The balance of deletion and regulation in allograft tolerance, Immunol Rev 196, 75–84 (2003).PubMedCrossRefGoogle Scholar
  42. 42.
    K. Kishimoto, V. M. Dong, S. Issazadeh, E. V. Fedoseyeva, et al., The role of CD154-CD40 versus CD28–B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo, J Clin Invest 106(1), 63–72 (2000).PubMedCrossRefGoogle Scholar
  43. 43.
    I. C. Rulifson, A. I. Sperling, P. E. Fields, F. W. Fitch, J. A. Bluestone, CD28 costimulation promotes the production of Th2 cytokines, J Immunol 158(2), 658–665 (1997).PubMedGoogle Scholar
  44. 44.
    Z. Dai, F. G. Lakkis, The role of cytokines, CTLA-4 and costimulation in transplant tolerance and rejection, Curr Opin Immunol 11(5), 504–508 (1999).PubMedCrossRefGoogle Scholar
  45. 45.
    X. C. Li, G. Demirci, S. Ferrari-Lacraz, C. Groves, A. Coyle, T. R. Malek, T. B. Strom, IL-15 and IL-2: a matter of life and death for T cells in vivo, Nat Med 7(1), 114–118 (2001).PubMedCrossRefGoogle Scholar
  46. 46.
    Y. Li, X. C. Li, X. X. Zheng, A. D. Wells, L. A. Turka, T. B. Strom, Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance, Nat Med 5(11), 1298–1302 (1999).PubMedCrossRefGoogle Scholar
  47. 47.
    G. Opelz, Correlation of HLA matching with kidney graft survival in patients with or without cyclosporine treatment, Transplantation 40(3), 240–243 (1985).PubMedCrossRefGoogle Scholar
  48. 48.
    W. P. Lee, M. J. Yaremchuk, Y. C. Pan, M. A. Randolph, C. M. Tan, A. J. Weiland, Relative antigenicity of components of a vascularized limb allograft, Plast Reconstr Surg 87(3), 401–411 (1991).PubMedCrossRefGoogle Scholar
  49. 49.
    C. Tai, M. Goldenberg, K. M. Schuster, B. R. Kann, C. W. Hewitt, Composite tissue allotransplantation, J Invest Surg 16(4), 193–201 (2003).PubMedCrossRefGoogle Scholar
  50. 50.
    S. E. Hovius, H. P. Stevens, P. W. van Nierop, W. Rating, R. van Strik, J. C. van der Meulen, Allogeneic transplantation of the radial side of the hand in the rhesus monkey: I. Technical aspects, Plast Reconstr Surg 89(4), 700–709 (1992).PubMedCrossRefGoogle Scholar
  51. 51.
    B. Yazdi, M. P. Patel, R. Ramsamooj, R. Llull, B. M. Achauer, K. S. Black, C. W. Hewitt, Vascularized bone marrow transplantation (VBMT): induction of stable mixed T-cell chimerism and transplantation tolerance in unmodified recipients, Transplant Proc 23(1 Pt 1), 739–740 (1991).PubMedGoogle Scholar
  52. 52.
    C. G. Francois, W. C. Breidenbach, C. Maldonado, T. P. Kakoulidis, et al., Hand transplantation: comparisons and observations of the first four clinical cases, Microsurgery 20(8), 360–371 (2000).PubMedCrossRefGoogle Scholar
  53. 53.
    W. P. Lee, J. P. Rubin, J. L. Bourget, S. R. Cober, M. A. Randolph, G. P. Nielsen, F. L. Ierino, D. H. Sachs, Tolerance to limb tissue allografts between swine matched for major histocompatibility complex antigens, Plast Reconstr Surg 107(6), 1482–1490; discussion 1491–1482 (2001).PubMedCrossRefGoogle Scholar
  54. 54.
    A. Geluk, D. G. Elferink, B. L. Slierendregt, K. E. van Meijgaarden, R. R. de Vries, T. H. Ottenhoff, R. E. Bontrop, Evolutionary conservation of major histocompatibility complex-DR/peptide/T cell interactions in primates, J Exp Med 177(4), 979–987 (1993).PubMedCrossRefGoogle Scholar
  55. 55.
    M. Siemionow, S. Unal, Strategies for tolerance induction in nonhuman primates, Ann Plast Surg 55(5), 545–553 (2005).PubMedCrossRefGoogle Scholar
  56. 56.
    R. K. Daniel, E. P. Egerszegi, D. D. Samulack, S. E. Skanes, R. W. Dykes, W. R. Rennie, Tissue transplants in primates for upper extremity reconstruction: a preliminary report, J Hand Surg [Am] 11(1), 1–8 (1986).Google Scholar
  57. 57.
    G. B. Stark, W. M. Swartz, K. Narayanan, A. R. Moller, Hand transplantation in baboons, Transplant Proc 19(5), 3968–3971 (1987).PubMedGoogle Scholar
  58. 58.
    H. P. Stevens, S. E. Hovius, V. D. Vuzevski, P. W. van Nierop, M. Gotte, N. A. Roche, M. Jonker, Immunological aspects of allogeneic partial hand transplantation in the rhesus monkey, Transplant Proc 22(4), 2006–2008 (1990).PubMedGoogle Scholar
  59. 59.
    H. P. Stevens, S. E. Hovius, J. L. Heeney, P. W. van Nierop, M. Jonker, Immunologic aspects and complications of composite tissue allografting for upper extremity reconstruction: a study in the rhesus monkey, Transplant Proc 23(1 Pt 1), 623–625 (1991).PubMedGoogle Scholar
  60. 60.
    M. E. Gold, J. Randzio, H. Kniha, B. S. Kim, H. H. Park, J. P. Stein, K. Booth, H. E. Gruber, D. W. Furnas, Transplantation of vascularized composite mandibular allografts in young cynomolgus monkeys, Ann Plast Surg 26(2), 125–132 (1991).PubMedCrossRefGoogle Scholar
  61. 61.
    W. P. Lee, J. P. Rubin, J. L. Bourget, S. R. Cober, M. A. Randolph, G. P. Nielsen, F. L. Ierino, D. H. Sachs, Tolerance to limb tissue allografts between swine matched for major histocompatibility complex antigens, Plast Reconstr Surg 107(6), 1482–1490; discussion 1491–1482 (2001).PubMedCrossRefGoogle Scholar
  62. 62.
    J. L. Bourget, D. W. Mathes, G. P. Nielsen, M. A. Randolph, et al., Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine, Transplantation 71(7), 851–856 (2001).PubMedCrossRefGoogle Scholar
  63. 63.
    S. T. Ildstad, D. H. Sachs, Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts, Nature 307(5947), 168–170 (1984).PubMedCrossRefGoogle Scholar
  64. 64.
    Y. Sharabi, D. H. Sachs, Engraftment of allogeneic bone marrow following administration of anti-T cell monoclonal antibodies and low-dose irradiation, Transplant Proc 21(1 Pt 1), 233–235 (1989).PubMedGoogle Scholar
  65. 65.
    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
  66. 66.
    T. Kawai, A. B. Cosimi, R. B. Colvin, J. Powelson, et al., Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys, Transplantation 59(2), 256–262 (1995).PubMedCrossRefGoogle Scholar
  67. 67.
    R. D. Foster, L. Fan, M. Neipp, C. Kaufman, et al., Donor-specific tolerance induction in composite tissue allografts, Am J Surg 176(5), 418–421 (1998).PubMedCrossRefGoogle Scholar
  68. 68.
    L. H. Buhler, T. R. Spitzer, M. Sykes, D. H. Sachs, et al., Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease, Transplantation 74(10), 1405–1409 (2002).PubMedCrossRefGoogle Scholar
  69. 69.
    T. R. Spitzer, F. Delmonico, N. Tolkoff-Rubin, S. McAfee, et al., Combined histocompatibility leukocyte antigen-matched donor bone marrow and renal transplantation for multiple myeloma with end stage renal disease: the induction of allograft tolerance through mixed lymphohematopoietic chimerism, Transplantation 68(4), 480–484 (1999).PubMedCrossRefGoogle Scholar
  70. 70.
    M. M. Durham, A. W. Bingaman, A. B. Adams, J. Ha, S. Y. Waitze, T. C. Pearson, C. P. Larsen, Cutting edge: administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning, J Immunol 165(1), 1–4 (2000).PubMedGoogle Scholar
  71. 71.
    T. Wekerle, J. Kurtz, H. Ito, J. V. Ronquillo, et al., Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment, Nat Med 6(4), 464–469 (2000).PubMedCrossRefGoogle Scholar
  72. 72.
    E. A. Elster, P. J. Blair, A. D. Kirk, Potential of costimulation-based therapies for composite tissue allotransplantation, Microsurgery 20(8), 430–434 (2000).PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Patricio Andrades
    • 1
  • Clement Asiedu
    • 2
  • Judith M. Thomas
    • 3
  1. 1.Division of Plastic and Reconstructive Surgery, Department of Surgery, Jose Jaoquin Aquirre Clinical HospitalUniversity of Chile School of MedicineSantiago
  2. 2.Department of SurgeryUniversity of Alabama at BirminghamBirmingham
  3. 3.Departments of Surgery and MicrobiologyUniversity of Alabama at Birmingham School of MedicineBirmingham

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