On the Road to Tolerance Induction in Composite Tissue Allotransplantation

  • Mark A. Hardy

In 1954, the first successful kidney transplant between identical twins opened the way for the clinical application of solid organ transplantation. Recognizing that transplantation between identical twins would not be the route to widespread relief of organ failure because of the unique avoidance of rejection, researchers directed attention to widening the donor pool. Allotransplantation was the goal and this implied a search for methods to prevent rejection and destruction of the transplant. Over time it became apparent that the use of immunosuppressive drugs carried associated toxicity along with it. The goal of many transplant clinicians and immunobiologists was to induce tolerance without altering the recipient's response to infection and other antigens.


Dendritic Cell Allograft Rejection Tolerance Induction Cardiac Allograft Allograft Survival 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    R. D. Owen, Immunogenetic consequences of vascular anastomoses between bovine twins, Science 102, 400–401 (1945).PubMedCrossRefGoogle Scholar
  2. 2.
    R. E. Billingham, L. Brent, P. B. Medawar, “Actively acquired tolerance” of foreign cells, Nature 172, 603–606 (1953).PubMedCrossRefGoogle Scholar
  3. 3.
    A. D. Hess, A. C. Fischer, Immune mechanisms in cyclosporine-induced syngeneic graft versus host disease, Transplantation 48, 895–900 (1989).PubMedCrossRefGoogle Scholar
  4. 4.
    P. Blaha, et al., The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with co stimulation blockade, Blood 101, 2886–2893 (2003).PubMedCrossRefGoogle Scholar
  5. 5.
    T. Fehr, M. Sykes, Tolerance induction in clinical transplantation, Transpl Immunol 13, 117–130 (2004).PubMedCrossRefGoogle Scholar
  6. 6.
    R. Lechler, J. Bluestone, Transplantation tolerance: putting the pieces together, Cur Opin Immunol 9, 631–633 (1997).CrossRefGoogle Scholar
  7. 7.
    A. D. Wells, X. C. Li, Y. Li, M. C. Walsh, X. X. Zheng, Z. Wu, G. Nunez, A. Tang, M. Sayegh, W. W., Hancock, T. B. Strom, L A. Turka. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance, Nat Med 5, 1303–1307 (1999).PubMedCrossRefGoogle Scholar
  8. 8.
    K. Kishimoto, S. Sandner, J. Imitola, M. Sho, Y. Li, P. B. Langmuir, D. M. Rothstein, T. B. Strom, L. A. Turka, M. H. Sayegh, Th1 cytokines, programmed cell death, and alloreactive T cell clone size in transplant tolerance, J Clin Invest 109, 1471–1479 (2002).PubMedGoogle Scholar
  9. 9.
    M. Sho, A. Yamada, N. Najafian, A. D. Salama, H. Harada, S. E. Sandner, A. Sanchez-Fueyo, X. X. Zheng, T. B. Strom, M. H. Sayegh, Physiological mechanisms of regulating alloimmunity: cytokines, CTLA-4, CD25+ cells, and the alloreactive T cell clone size, J Immunol 169, 3744–3751 (2002).PubMedGoogle Scholar
  10. 10.
    N. E. Phillips, T. G. Markees, J. P. Mordes, D. L. Greiner, A. A. Rossini, Blockade of CD40-mediated signaling is sufficient for inducing islet but not skin transplantation tolerance, J Immunol 170, 3015–3023 (2003).PubMedGoogle Scholar
  11. 11.
    M. A. Williams, J. Trambley, J. Ha, A. B. Adams, M. M. Durham, P. Rees, S. R. Cowan, T. C. Pearson, C. P. Larsen, Genetic characterization of strain differences in the ability to mediate CD40/CD28-independent rejection of skin allografts, J Immunol 165, 6849–6857 (2000).PubMedGoogle Scholar
  12. 12.
    A. van Maurik, K. J. Wood, N. D. Jones, Impact of both donor and recipient strains on cardiac allograft survival after blockade of the CD40-CD154 costimulatory pathway, Transplantation 74, 740–743 (2002).PubMedCrossRefGoogle Scholar
  13. 13.
    E. Suri-Payer, A. Z. Amar, A. M. Thornton, E. M. Shevach, CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells, J Immunol 160, 1212–1218 (1998).PubMedGoogle Scholar
  14. 14.
    F. Powrie, R. Correa-Oliveira, S. Mauze, R. L. Coffman, Regulatory interactions between CD45RBhigh and CD45RBIow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity, J Exp Med 179, 589–600 (1994).PubMedCrossRefGoogle Scholar
  15. 15.
    M. Papiernik, M. L. de Moraes, C. Pontoux, F. Vasseur, C. Penit, Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and lL-2 dependency, Int Immunol, 10, 371–378 (1998).PubMedCrossRefGoogle Scholar
  16. 16.
    K. M. Thorstenson, A. Khoruts, Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen, J Immunol 167, 188–195 (2001).PubMedGoogle Scholar
  17. 17.
    J. D. Fontenot, M. A. Gavin, A. Y. Rudensky, FoxpS programs the development and function of CD4+CD25+ regulatory T cells, Nat Immunol 4, 330–336 (2003).PubMedCrossRefGoogle Scholar
  18. 18.
    J. D. Fontenot, J. P. Rasmussen, L. M. Williams, J. L. Dooley, A. G. Farr, A. Y. Rudensky, Regulatory T cell lineage specification by the forkhead transcription factor foxpS, Immunity 22, 329–341 (2005).PubMedCrossRefGoogle Scholar
  19. 19.
    L. S. Walker, A. Chodos, M. Eggena, H. Dooms, A. K. Abbas, Antigen-dependent proliferation of CD4+CD25+ regulatory T cells in vivo, J Exp Med 198, 249–258 (2003).PubMedCrossRefGoogle Scholar
  20. 20.
    L. Klein, K. Khazaie, H. von Boehmer, In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro, Proc Natl Acad Sci USA 100, 8886–8891 (2003).PubMedCrossRefGoogle Scholar
  21. 21.
    E. Nishimura, T. Sakihama, R. Setoguchi, K. Tanaka, S. Sakaguchi, Induction of antigenspecific immunologic tolerance by in vivo and in vitro antigen-specific expansion of naturally arising Foxp3+CD25+CD4+ regulatory T cells, Int Immunol 16, 1189–1201 (2004).PubMedCrossRefGoogle Scholar
  22. 22.
    H. Groux, A. O’Garra, M. Bigler, M. Rouleau, S. Antonenko, J. E. de Vries, M. G. Roncarolo, A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis, Nature 389, 737–742 (1997).PubMedCrossRefGoogle Scholar
  23. 23.
    F. J. Barrat, D. J. Cua, A. Boonstra, D. F. Richards, C. Grain, H. F. Savelkoul, R. de Waal-Malefyt, R. L. Coffman, C. M. Hawrylowicz, A. O’Garra, In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines, J Exp Med 195, 603–616 (2002).PubMedCrossRefGoogle Scholar
  24. 24.
    P. L. Vieira, J. R. Christensen, S. Minaee, E. J. O’Neill, F. J. Barrat, A. Boonstra, T. Barthlott, B. Stockinger, D. C. Wraith, A. O’Garra, IL-10-secreting regulatory T cells do not express FoxpS but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells, J Immunol 172, 5986–5993 (2004).PubMedGoogle Scholar
  25. 25.
    K. J. Wood, S. Sakaguchi, Regulatory T cells in transplantation tolerance, Nat Rev Immunol 3, 199–210 (2003).PubMedCrossRefGoogle Scholar
  26. 26.
    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
  27. 27.
    H. Waldmann, L. Graca, S. Cobbold, E. Adams, M. Tone, Y. Tone, Regulatory T cells and organ transplantation. Semin Immunol 16, 119–126 (2004).PubMedCrossRefGoogle Scholar
  28. 28.
    A. Proneth, B. G. Exner, J. H. Fechner, E. K. Geissler, F. Fandrich, S. J. Knechtle, Monocyte-dervided cells from monkeys induce regulatory cells in vitro: a potential new cell therapy approach for transplant tolerance, Am J Transpl Transplant (supplement WCT Congress Abstracts) 1621, 608 (2006).Google Scholar
  29. 29.
    N. Suciu-Foca, J. S. Manavalan, R. Cortesini, Generation and function of antigen-specificsuppressor and regulatory T cells, Transpl Immunol 11, 235 (2003).PubMedCrossRefGoogle Scholar
  30. 30.
    Z. Liu, S. Tugulea, R. Cortesini, N. Suciu-Foca, Specific suppression of T helper alloreactivity by allo-MHC class I-restricted CD8+CD28- T cells, Int Immunol 10, 775 (1998).PubMedCrossRefGoogle Scholar
  31. 31.
    R. Ciubotariu, A. I. Colovai, G. Pennesi, Z. Liu, D. Smith, P. Berlocco, R. Cortesini, N. Suciu-Foca, Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+CD28- regulatory T cells, J Immunol 161, 5193 (1998).PubMedGoogle Scholar
  32. 32.
    S. Jiang, S. Tugulea, G. Pennesi, Z. Liu, A. Mulder, S. Lederman, P. Harris, R. Cortesini, N. Suciu-Foca, Induction of MHC-class I restricted human suppressor T cells by peptide priming in vitro, Hum Immunol 59, 690 (1998).PubMedCrossRefGoogle Scholar
  33. 33.
    A. I. Colovai, Z. Liu, R. Ciubotariu, S. Lederman, R. Cortesini, N. Suciu-Foca, Induction of xenoreactive CD4+ T-cell anergy by suppressor CD8+CD28- T cells, Transplantation 69, 1304 (2000).PubMedCrossRefGoogle Scholar
  34. 34.
    Z. Liu, S. Tugulea, R. Cortesini, S. Lederman, N. Suciu-Foca, Inhibition of CD40 signaling pathway in antigen presenting cells by T suppressor cells, Hum Immunol 60, 568 (1999).PubMedCrossRefGoogle Scholar
  35. 35.
    J. Li, Z. Liu, S. Jiang, R. Cortesini, S. Lederman, N. Suciu-Foca, T suppressor lymphocytes inhibit NF-kappa B-mediated transcription of CD86 gene in APC, J Immunol 163, 6386 (1999).PubMedGoogle Scholar
  36. 36.
    C. C. Chang, R. Ciubotariu, J. S. Manavalan, J. Yuan, A. I. Colovai, F. Piazza, S. Lederman, M. Colonna, R. Cortesini, R. Dalla-Favera, N. Suciu-Foca, Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4, Nat Immunol 3, 237 (2002).PubMedCrossRefGoogle Scholar
  37. 37.
    N. Suciu-Foca Cortesini, F. Piazza, E. Ho, R. Ciubotariu, J. LeMaoult, R. Dalla-Favera, R. Cortesini, Distinct mRNA microarray profiles of tolerogenic dendritic cells, Hum Immunol 62, 1065 (2001).PubMedCrossRefGoogle Scholar
  38. 38.
    R. Cortesini, J. LeMaoult, R. Ciubotariu, N. S. Cortesini, CD8+CD28- T suppressor cells and the induction of antigen-specific, antigen-presenting cell-mediated suppression of Th reactivity, Immunol Rev 182, 201 (2001).PubMedCrossRefGoogle Scholar
  39. 39.
    A. I. Colovai, M. Mirza, G. Vlad, S. Wang, E. Ho, R. Cortesini, N. Suciu-Foca, Regulatory CD8+CD28- T cells in heart transplant recipients, Hum Immunol 64, 31 (2003).PubMedCrossRefGoogle Scholar
  40. 40.
    R. Ciubotariu, R. Vasilescu, E. Ho, P. Cinti, C. Cancedda, L. Poli, M. Late, Z. Liu, P. Berloco, R. Cortesini, N. Suciu-Foca Cortesini, Detection of T suppressor cells in patients with organ allografts, Hum Immunol 62, 15 (2001).PubMedCrossRefGoogle Scholar
  41. 41.
    R. Cortesini, E. Renna-Molajoni, P. Cinti, R. Pretagostini, E. Ho, P. Rossi, N. Suciu-Foca Cortesini, Tailoring of immunosuppression in renal and liver allograft recipients displaying donor specific T suppressor cells, Hum Immunol 63, 1010 (2002).PubMedCrossRefGoogle Scholar
  42. 42.
    J. S. Manavalan, P. C. Rossi, G. Vlad, F. Piazza, A. Yarilina, R. Cortesini, D. Mancini, N. Suciu-Foca, High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells, Transpl Immunol 11, 245 (2003).PubMedCrossRefGoogle Scholar
  43. 43.
    J. S. Manavalan, S. Kim-Schulze, L. Scotto, A. J. Naiyer, G. Vlad, P. C. Colombo, C. Marboe, D. Mancini, R. Cortesini, N. Suciu-Foca, Alloantigen specific CD8+CD28- FOXP3+ T suppressor cells induce ILT3+ILT4+ tolerogenic endothelial cells, inhibiting alloreactivity, Int Immunol 16, 1055 (2004).PubMedCrossRefGoogle Scholar
  44. 44.
    M. K. Jenkins, The ups and downs of T cell costimulation, Immunity 1, 443–446 (1994).PubMedCrossRefGoogle Scholar
  45. 45.
    R. J. Greenwald, G. J. Freeman, A. M. Sharpe, The B7 family revisited, Ann Rev Immunol 23, 515–548 (2005).CrossRefGoogle Scholar
  46. 46.
    S. A. Quezada, L. Z. Jarvinen, E. F. Lind, R. J. Noelle, CD40/CD154 interactions at the interface of tolerance and immunity, Ann Rev Immunol 22, 307–328 (2004).CrossRefGoogle Scholar
  47. 47.
    T. C. Pearson, D. Z. Alexander, M. Corbascio, R. Hendrix, S. C. Ritchie, P. S. Linsley, D. Faherty, C. P. Larsen, Analysis of the B7 costimulatory pathway in allograft rejection, Transplantation 63, 1463–1469 (1997).PubMedCrossRefGoogle Scholar
  48. 48.
    T. C. Pearson, D. Z. Alexander, K. J. Winn, P. S. Linsley, R. P. Lowry, C. P. Larsen, Transplantation tolerance induced by CTLA4-Ig, Transplantation 57, 1701–1706 (1994).PubMedGoogle Scholar
  49. 49.
    M. H. Sayegh, E. Akalin, W. W. Hancock, M. E. Russell, C. B. Carpenter, P. S. Linsley, L. A. Turka, CD28–B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2, J Exp Med 181, 1869–1874 (1995).PubMedCrossRefGoogle Scholar
  50. 50.
    D. Lenschow, Y. Zeng, J. Thistlethwaite, A. Montag, W. Brady, M. Gibson, P. Linsley, J. Bluestone, Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4Ig, Science 257, 789–792 (1992).PubMedCrossRefGoogle Scholar
  51. 51.
    A. D. Kirk, D. M. Harlan, N. N. Armstrong, T. A. Davis, Y. Dong, G. S. Gray, X. Hong, D. Thomas, J. H. Fechner, S. J. Knechtle, CTLA4-Ig and anti-CD40L prevent renal allograft rejection in primates, Proc Natl Acad Sci USA 94, 8789–8794 (1997).PubMedCrossRefGoogle Scholar
  52. 52.
    M. G. Levisetti, P. A. Padrid, G. L. Szot, N. Mittal, S. M. Meehan, C. L. Wardrip, G. S. Gray, D. S. Bruce, J. R. Thistlethwaite, Jr., J. A. Bluestone, Immunosuppressive effects of human CTLA4Ig in a non-human primate model of allogeneic pancreatic islet transplantation, J Immunol 159, 5187–5191 (1997).PubMedGoogle Scholar
  53. 53.
    C. P. Larsen, T. C. Pearson, A. B. Adams, P. Tso, N. Shirasugi, E. Strobertm, D. Anderson, S. Cowan, K. Price, J. Naemura, J. Emswiler, J. Greene, L. A. Turk, J. Bajorath, R. Townsend, D. Hagerty, P. S. Linsley, R. J. Peach, Rational development of LEA29Y (Belatacept©), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties, Am J Transplant 5, 443–453 (2005).PubMedCrossRefGoogle Scholar
  54. 54.
    F. Vincenti, C. Larsen, A. Durrbach, T. Wekerle, B. Nashan, G. Blanche, P. Lang, J. Grinyo, P. P. Halloran, K. Solez, D. Hagerty, E. Levy, W. Zhou, K. Natarajan, B. Charpentier, Costimulation blockade with belatacept in renal transplantation, N Engl J Med 353, 770–781 (2005).PubMedCrossRefGoogle Scholar
  55. 55.
    T. Wekerle, J. Kurtz, S. Bigenzahn, Y. Takeuchi, M. Sykes, Mechanisms of transplant tolerance induction using costimulatory blockade, Curr Opin Immunol 14, 592 (2002).PubMedCrossRefGoogle Scholar
  56. 56.
    M. R. Clarkson, M. H. Sayegh, T-cell costimulatory pathways in allograft rejection and tolerance, Transplantation 80, 555 (2002).CrossRefGoogle Scholar
  57. 57.
    K. Honey, S. P. Cobbold, H. Waldmann, CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression, J Immunol 163, 4805 (1999).PubMedGoogle Scholar
  58. 58.
    L. Graca, K. Honey, E. Adams, S. P. Cobbold, H. Waldmann, Cutting edge: anti-GDI 54 therapeutic antibodies induce infectious transplantation tolerance, J Immunol 165, 4783 (2000).PubMedGoogle Scholar
  59. 59.
    S. A. Quezada, K. Bennett, B. R. Blazar, A. Y. Rudensky, S. Sakaguchi, R. J. Noelle, Analysis of the underlying cellular mechanisms of anti-GDI 54-induced graft tolerance: the interplay of clonal anergy and immune regulation, J Immunol 175, 771 (2005).PubMedGoogle Scholar
  60. 60.
    P. I. Sidiropoulos, D. T. Boumpas, Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients, Lupus 13, 391 (2004).PubMedCrossRefGoogle Scholar
  61. 61.
    K. G. Haanstra, E. A. Sick, J. Ringers, J. A. Wubben, E. M. Kuhn, L. Boon, M. Jonker, Costimulation blockade followed by a 12-week period of cyclosporine A facilitates prolonged drug-free survival of rhesus monkey kidney allografts, Transplantation 79, 1623 (2005).PubMedCrossRefGoogle Scholar
  62. 62.
    A. B. Adams, N. Shirasugi, T. R. Jones, M. M. Durham, E. A. Strobert, S. Cowan, P. Rees, R. Hendrix, K. Price, N. S. Kenyon, D. Hagerty, R. Townsend, D. Hollenbaugh, T. C. Pearson, C. P. Larsen, Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival, J Immunol 174, 542 (2005).PubMedGoogle Scholar
  63. 63.
    C. P. Larsen, et al., CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway, Transplantation 61, 4–9 (1996).PubMedCrossRefGoogle Scholar
  64. 64.
    C. P. Larsen, et al., Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways, Nature 381, 434–438 (1996).PubMedCrossRefGoogle Scholar
  65. 65.
    Y. Li, X. X. Zheng, X. C. Li, M. S. Zand, T. B. Strom, Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment, Transplantation 66, 1387–1388 (1998).PubMedCrossRefGoogle Scholar
  66. 66.
    C. B. Anderson, et al., Beneficial effects of donor-specific transfusions on long-term renal allograft function, Transplant Proc 27, 991–994 (1995).PubMedGoogle Scholar
  67. 67.
    M. L. Wood, R. Gottschalk, A. P. Monaco, Comparison of immune responsiveness in mice after single or multiple donor-specific transfusions, J Immunol 132, 651–655 (1984).PubMedGoogle Scholar
  68. 68.
    S. F. Oluwole, C. Iga, H. Lau, M. A. Hardy, Prolongation of rat heart allografts by donor-specific blood transfusion treated with ultraviolet irradiation, Heart Transplantation 4, 385–389 (1985).Google Scholar
  69. 69.
    S. F. Oluwole, J. Chabot, P. Pepino, K. Reemtsma, M. A. Hardy, Mechanisms of immunologic unresponsiveness induced by UV-irradiated donor-specific blood transfusions and peritransplant cyclosporine, Transplantation 46, 352–358 (1988).PubMedCrossRefGoogle Scholar
  70. 70.
    S. F. Oluwole, K. Reemtsma, M. A. Hardy, Characteristics and function of suppressor T-lymphocytes in immunologically unresponsive rats following pretreatment with UV-B-irradiated donor leukocytes and peritransplant Cyclosporine, Transplantation 47, 1001–1007 (1989).PubMedCrossRefGoogle Scholar
  71. 71.
    M. A. Hardy, S. F. Oluwole, Effect of ultraviolet radiation on immunogenicity of tissues and organ allografts, Transplant Rev 5, 46–62 (1991).CrossRefGoogle Scholar
  72. 72.
    D. C. Parker, et al., Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand, Proc Natl Acad Sci USA 92, 9560–9564 (1995).PubMedCrossRefGoogle Scholar
  73. 73.
    H. A. DePaz, O. O. Oluwole, A. O. Adeveri, P. Witkowski, M. X. Jin, M. A. Hardy, S. F. Oluwole, Immature rat myeloid dendritic cells generated in low dose granulocyte macrophage–colony stimulating factor prolong donor-specific rat cardiac allograft survival, Transplantation 75, 521–528 (2003).PubMedCrossRefGoogle Scholar
  74. 74.
    O. O. Oluwole, H. A. DePaz, A. Adeyeri, M. X. Jin, M. A. Hardy, S. F. Oluwole, Role of CD4+CD25+ regulatory T cells from naïve host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide, Transplantation 75, 1136–1142 (2003).PubMedCrossRefGoogle Scholar
  75. 75.
    A. Mondino, A. Khoruts, M. K. Jenkins, The anatomy of T-cell activation and tolerance, Proc Natl Acad Sci USA 93, 2245–2252 (1996).PubMedCrossRefGoogle Scholar
  76. 76.
    C. P. O’Larsen, P. J. Morris, J. M. Austyn, Migration of dendritic leukocytes from cardiac allografts into host spleens, J. Exp. Med. 171, 307–314 (1990).CrossRefGoogle Scholar
  77. 77.
    Z. Wang, A. Castellaneta, A. D. Creus, W. J. Shufesky, A. E. Morelli, A. W. Thomson, Heart, but not skin allografts from donors lacking Flt3 ligand exhibit markedly prolonged survival time, J Immunol 172, 5924–5930 (2004).PubMedGoogle Scholar
  78. 78.
    M. Baratin, K. Bonin, C. Daniel, Frontline: peripheral priming of alloreactive T cells by the direct pathway of allorecognition, Eur J Immunol 34, 3305–3314 (2004).PubMedCrossRefGoogle Scholar
  79. 79.
    R. M. Steinman, D. Hawiger, M. C. Nussenzweig, Tolerogenic dendritic cells, Annu Rev Immunol 21, 685–711 (2003).PubMedCrossRefGoogle Scholar
  80. 80.
    M. V. Dhodapkar, R. M. Steinman, J. Krasovsky, C. Munz, N. Bhardwaj, Antigenspecific inhibition of effector T cell function in humans after injection of immature dendritic cells, J Exp Med 193, 233–238 (2001).PubMedCrossRefGoogle Scholar
  81. 81.
    Z. X. Lian, T. Okada, X. S. He, H. Kita, Y. J. Liu, A. A. Ansari, K. Kikuchi, S. Ikehara. M. E. Gershwin, Heterogeneity of dendritic cells in the mouse liver: identification and characterization of four distinct populations, J Immunol 170, 2323–2330 (2003).PubMedGoogle Scholar
  82. 82.
    Y. J. Liu, H. Kanzler, V. Soumelis, M. Gilliet, Dendritic cell lineage, plasticity and cross-regulation, Nat Immunol 2, 585–589 (2001).PubMedCrossRefGoogle Scholar
  83. 83.
    L. Lu, A. W. Thomson, Dendritic cell tolerogenicity and prospects for dendritic cell-based therapy of allograft rejection and autoimmune disease. In Dendritic Cells, Second Edition. M. T. Lotze, A. W. Thomson, editors. Academic Press, San Diego, pp. 587–607 (2001).Google Scholar
  84. 84.
    R. I. Lechler, W. F. Ng, R. M. Steinman, Dendritic cells in transplantation – friend or foe, Immunity 14, 357–368 (2001).PubMedCrossRefGoogle Scholar
  85. 85.
    A. W. Thomson, L. Lu, Dendritic cells as regulators of immune reactivity: implications for transplantation, Transplantation 68, 1–8 (1999).PubMedCrossRefGoogle Scholar
  86. 86.
    M. H. Sayegh, N. Perico, L. Gallon, O. Imberti, W. W. Hancock, G. Remuzzi, C. B. Carpenter, Mechanisms of acquired thymic unresponsiveness to renal allografts. Thymic recognition of immunodominant allo-MHC peptides induces peripheral T cell anergy, Transplantation 58, 125–132 (1994).PubMedGoogle Scholar
  87. 87.
    M. Garrovillo, A. Ali, H. A. Depaz, R. Gopinathan, O. O. Oluwole, M. A. Hardy, S. F. Oluwole, Induction of transplant tolerance with immunodominant allopeptide-pulsed host lymphoid and myeloid dendritic cells, Am J Transplant 1, 129–137 (2001).PubMedCrossRefGoogle Scholar
  88. 88.
    M. Garrovillo, A. Ali, S. F. Oluwole, M. A. Hardy, Indirect allorecognition in acquired thymic tolerance: induction of donor-specific tolerance to rat cardiac allografts by allopeptide-pulsed host dendritic cells, Transplantation 68, 1827–1834 (1999).PubMedCrossRefGoogle Scholar
  89. 89.
    A. Ali, M. Garrovillo, M. X. Jin, M. A. Hardy, S. F. Oluwole, Major histocompatibility complex class I peptide-pulsed host dendritic cells induce antigen-specific acquired thymic tolerance to islet cells, Transplantation 69, 221–226 (2000).PubMedCrossRefGoogle Scholar
  90. 90.
    S. F. Oluwole, O. O. Oluwole, H. A. DePaz, A. O. Adeyeri, P. Witkowski, M. A. Hardy, CD4+CD25+ regulatory T cells mediate acquired transplant tolerance, Transpl Immunol 11, 287–293 (2003).PubMedCrossRefGoogle Scholar
  91. 91.
    P. Kalinski, C. M. Hilkens, E. A. Wierenga, M. L. Kapsenberg, T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal, Immunol Today 20, 561–567 (1999).PubMedCrossRefGoogle Scholar
  92. 92.
    J. I. Lee, R. W. Ganster, D. A. Geller, G. J. Burckart, A. W. Thomson, L. Lu, Cyclosporine A inhibits the expression of costimulatory molecules on in vitro-generated dendritic cells: association with reduced nuclear translocation of nuclear factor kappa B, Transplantation 68, 1255–1263 (1999).PubMedCrossRefGoogle Scholar
  93. 93.
    T. Hackstein, T. Taner, A. F. Zahorchak, A. E. Morelli, A. J. Logar, A. Gessner, A. W. Thomson, Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo, Blood 101, 4457–4463 (2003).PubMedCrossRefGoogle Scholar
  94. 94.
    A. Mehling, S. Grabbe, M. Voskort, T. Schwarz, T. A. Luger, S. Beissert, Mycophenolate mofetil impairs the maturation and function of murine dendritic cells, J Immunol 165, 2374–2381 (2000).PubMedGoogle Scholar
  95. 95.
    G. Penna, L. Adorini, 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation, J Immunol 164, 2405–2411 (2000).PubMedGoogle Scholar
  96. 96.
    A. W. Thomson, L. Lu, Are dendritic cells the key to liver transplant tolerance? Immunol Today 20, 27–32 (1999).PubMedCrossRefGoogle Scholar
  97. 97.
    J. Banchereau, F. Briere, C. Caux, J. Davoust, S. Lebecque, Y. J. Liu, B. Pulendran, K. Palucka, Immunobiology of dendritic cells, Ann Rev Immunol 18, 767–811 (2000).CrossRefGoogle Scholar
  98. 98.
    P. T. Coates, A. W. Thomson, Dendritic cells, tolerance induction and transplant outcome, Am J Transplant 2, 299–307 (2002).PubMedCrossRefGoogle Scholar
  99. 99.
    R. J. Steptoe, A. W. Thomson, Dendritic cells and tolerance induction, Clin Exp Immunol 105, 397–402 (1996).PubMedCrossRefGoogle Scholar
  100. 100.
    R. I. Lechler, J. R. Batchelor, Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells, J Exp Med 155, 31–41 (1992).CrossRefGoogle Scholar
  101. 101.
    D. Talmage, G. Dart, J. Radovich, K. Lafferty, Activation of transplant immunity: effect of donor leucocytes on thyroid allograft rejection, Science 191, 385–388 (1976).PubMedCrossRefGoogle Scholar
  102. 102.
    M. Rouabhia, L. Germain, F. Belanger, F. A. Auger, Cultured epithelium allografts: Langerhans cell and Thy-l+ dendritic epidermal cell depletion effects on allograft rejection, Transplantation 56, 259–264 (1993).PubMedCrossRefGoogle Scholar
  103. 103.
    T. E. Starzl, A. J. Demetris, N. Murase, S. Ildstad, C. Ricordi, M. Trucco, Cell migration, chimerism, and graft acceptance, Lancet 339, 1579–1582 (1992).PubMedCrossRefGoogle Scholar
  104. 104.
    M. J. Kuwana, J. Kaburaki, T. M. Wright, Y. Kawakami, Y. Ikeda, Induction of antigen-specific human CD4(+) T cell anergy by peripheral blood DC2 precursors, Eur J Immunol 31, 2547–2557 (2001).PubMedCrossRefGoogle Scholar
  105. 105.
    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, 168–170 (1984).PubMedCrossRefGoogle Scholar
  106. 106.
    M. Sykes, D. H. Sachs, Mixed chimerism, Philos Trans R Soc Lond B Biol Sci 356, 707–726 (2001).PubMedCrossRefGoogle Scholar
  107. 107.
    E. H. Field, S. Strober, Tolerance, mixed chimerism and protection against GVHD after TLI, Philos Trans R Soc Lond Biol Sci 356, 1–10 (2001).Google Scholar
  108. 108.
    S. Strober, R. J. Lowsky, J. A. Shizuru, J. D. Scandling, M. T. Millan, Approaches to transplantation tolerance in humans, Transplantation 77, 932–936 (2004).PubMedCrossRefGoogle Scholar
  109. 109.
    L. H. Buhler, T. R. Spitzer, M. Sykes, D. H. Sachs, F. L. Delmonico, N. Tolkoff-Rubin, S. L. Saidman, R. Sackstein, S. McAfee, B. Dey, C. Colby, A. B. Cosimi, Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease, Transplantation 74, 1405–1409 (2002).PubMedCrossRefGoogle Scholar
  110. 110.
    A. B. Cosimi, D. H. Sachs, Mixed chimerism and transplantation tolerance, Transplantation 77, 943–946 (2004).PubMedCrossRefGoogle Scholar
  111. 111.
    J. W. Kappler, N. Roehm, P. Marrack, T cell tolerance by clonal elimination in the thymus, Cell 49, 273–276 (1987).PubMedCrossRefGoogle Scholar
  112. 112.
    P. Nickerson, W. Streurer, J. Steiger, T. B. Strom, In pursuit of the “Holy Grail”: Allograft tolerance, Kidney Intl 45, 840–49 (1994).Google Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Mark A. Hardy
    • 1
  1. 1.Columbia UniversityNew York

Personalised recommendations