Skip to main content
SpringerLink
Log in

Regulatory T Cells in Transplantation

  • Chapter
  • First Online:
Regulatory T Cells and Clinical Application

  • 746 Accesses

Abstract

Clinical success in treating transplant rejection to date has been achieved primarily through the development increasingly potent immunosuppressive drugs to inhibit immune responses. These approaches require life-long treatment and suppress the entire immune system non-specifically exposing the patient to increased risks of cancer and infection. Even then long-term graft survival is not guaranteed. Evidence that regulatory T cells can control rejection and facilitate the development of specific unresponsiveness to alloantigens in vivo has been accumulating over many years. Understanding how the immune system is controlled by regulatory T cells when it responds to alloantigen and promoting the development of cells that can regulate immune responses holds the key to the development of more selective therapies that target only destructive immune responses while leaving the beneficial protective functions of the immune system intact.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Billingham, R.E., L. Brent, and P.B. Medawar. 1953. Actively acquired tolerance of foreign cells. Nature 172:603–606.

    Article  PubMed  CAS  Google Scholar 

  2. Billingham, R.E., L. Brent, and P.B. Medawar. 1956. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Philos trans R Soc Lond B 239:357–412.

    Article  Google Scholar 

  3. Sakaguchi, S., N. Sakaguchi, M. Asano, M. Itoh, and M. Toda. 1995. Immunologic self tolerance maintained by activated T cells expressing IL-2 receptor alpha chains (CD25). Breakdown of a single mechanism of self tolerance causes various autoimmune diseases. J Immunol 155:1151–1164.

    PubMed  CAS  Google Scholar 

  4. Suri-Payer, E., A. Amar, A. Thornton, and E. Shevach. 1998. 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.

    PubMed  CAS  Google Scholar 

  5. Baecher-Allan, C., J. Brown, G. Freeman, and D. Hafler. 2001. CD4+ CD25+ high regulatory cells in human peripheral blood. J Immunol 167:1245–1253.

    PubMed  CAS  Google Scholar 

  6. Stephens, L., C. Mottet, D. Mason, and F. Powrie. 2001. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol 31: 1247–1254.

    Article  PubMed  CAS  Google Scholar 

  7. Hara, M., C. Kingsley, M. Niimi, S. Read, S. Turvey, A. Bushell, P. Morris, F. Powrie, and K. Wood. 2001. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 166:3789–3796.

    PubMed  CAS  Google Scholar 

  8. Thorstenson, K., and A. Khoruts. 2001. Generation of anergic and potentially immunoregulatory CD25+CD4+ T cells in vivo after induction of peripheral tolerance with intravenous oral antigen. J Immunol 167:188–195.

    PubMed  CAS  Google Scholar 

  9. Kingsley, C.I., M. Karim, A.R. Bushell, and K.J. Wood. 2002. CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses. J Immunol 168:1080–1086.

    PubMed  CAS  Google Scholar 

  10. Apostolou, I., and H. Von Boehmer. 2004. In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199:1401–1408.

    Article  PubMed  CAS  Google Scholar 

  11. Cobbold, S.P., R. Castejon, E. Adams, D. Zelenika, L. Graca, S. Humm, and H. Waldmann. 2004. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172:6003–6010.

    PubMed  CAS  Google Scholar 

  12. Marangoni, F., S. Trifari, S. Scaramuzza, C. Panaroni, S. Martino, L.D. Notarangelo, Z. Baz, A. Metin, F. Cattaneo, A. Villa, A. Aiuti, M. Battaglia, M.-G. Roncarolo, and L. Dupre. 2007. WASP regulates suppressor activity of human and murine CD4+CD25+FOXP3+ natural regulatory T cells. J Exp Med 204:369–380.

    Google Scholar 

  13. Long, E., and K.J. Wood. 2007. Understanding FOXP3: progress towards achieving transplantation tolerance. Transplantation 84:459–461.

    Article  PubMed  CAS  Google Scholar 

  14. Williams, L., and A. Rudensky. 2007. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8:277–284.

    Google Scholar 

  15. Wan, Y., and R. Flavell. 2007. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445:766–770.

    Google Scholar 

  16. Floess, S., J. Freyer, C. Siewert, U. Baron, S. Olek, J.K. Polansky, K. Schlawe, H.-D. Chang, T. Bopp, E. Schmitt, S. Klein-Hessling, E. Serfling, A. Hamann, and J. Huehn. 2007. Epigenetic control of the foxp3 locus in regulatory T cells. PLOS Biol 5:169–178

    Article  CAS  Google Scholar 

  17. Bushell, A., P. Morris, and K. Wood. 1995. Transplantation tolerance induced by antigen pretreatment and depleting anti-CD4 antibody depends on CD4+ T cell regulation during the induction phase of the response. Eur J Immunol 25:2643–2649.

    Article  PubMed  CAS  Google Scholar 

  18. Warnecke, G., A. Bushell, S. Nadig, and K.J. Wood. 2007. Regulation of transplant arteriosclerosis by CD25+CD4+ T cells generated to alloantigen in vivo. Transplantation 83:1459–1465.

    Google Scholar 

  19. Koshiba, T., T. Kitade, and B. Van Damme. 2003. Regulatory cell-mediated tolerance does not protect against chronic rejection. Transplantation 76:588–596.

    Article  CAS  Google Scholar 

  20. Weaver, C., L. Harrington, P. Mangan, M. Gavrieli, and K. Murphy. 2006. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688.

    Article  PubMed  CAS  Google Scholar 

  21. Wells, A., X. Li, Y. Li, M. Walsh, X. Zheng, Z. Wu, G. Nunez, A. Tang, M. Sayegh, W. Hancock, T. Strom, and L. Turka. 1999. Requirement for T cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 5:1303–1307.

    Article  PubMed  CAS  Google Scholar 

  22. Adams, A., M.A. Williams, T. Jones, N. Shiasugi, M.M. Durham, S. Kaech, E. Wherry, T. Onami, J. Lanier, K. Kokko, T. Pearson, R. Ahmed, and C.P. Larsen. 2003. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 111:1887–1895.

    PubMed  CAS  Google Scholar 

  23. Yang, J., M. Brook, M. Carvalho-Gaspar, J. Zhang, H. Ramon, M. Sayegh, K. Wood, L. Turka, and N. Jones. 2007. Allograft rejection mediated by memory T cells is resistant to regulation. Proc Natl Acad Sci USA 104:19954–19959.

    Article  PubMed  CAS  Google Scholar 

  24. Tang, Q., J. Adams, A. Tooley, M. Bi, B. Fife, P. Serra, P. Santamaria, R. Locksley, M. Krummel, and J. Bluestone. 2006. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7:83–92.

    Article  PubMed  CAS  Google Scholar 

  25. Veldhoen, M., R. Hocking, C. Atkins, R. Locksley, and B. Stockinger. 2006. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189.

    Article  PubMed  CAS  Google Scholar 

  26. Bettelli, E., Y. Carrier, W. Gao, T. Korn, T. Strom, M. Oukka, H. Weiner, and V. Kuchroo. 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238.

    Article  PubMed  CAS  Google Scholar 

  27. Pratschke, J., M.J. Wilhelm, I. Laskowski, M. Kusaka, F. Beato, S.G. Tullius, P. Neuhaus, W.W. Hancock, and N.L. Tilney. 2001. Influence of donor brain death on chronic rejection of renal transplants in rats. J Am Soc Nephrol 12:2474–2481.

    PubMed  CAS  Google Scholar 

  28. Weiss, S., K. Kotsch, M. Francuski, A. Reutzel-Selke, L. Mantouvalou, R. Klemz, O. Kuecuek, S. Jonas, C. Wesslau, F. Ulrich, A. Pascher, H.D. Volk, S.G. Tullius, P. Neuhaus, and J. Pratschke. 2007. Brain death activates donor organs and is associated with a worse I/R injury after liver transplantation. Am J Transplant 7:1584–1593.

    Article  PubMed  CAS  Google Scholar 

  29. Pratschke, J., D. Paz, M. Wilhelm, I. Laskowski, G. Kofla, A. Vergopoulos, H. MacKenzie, S. Tullius, P. Neuhaus, W.W. Hancock, H.-D. Volk, and N. Tilney. 2004. Donor hypertension increases graft immunogenicity and intensifies chronic changes in long-surviving renal allografts. Transplantation 77:43–48.

    Article  PubMed  CAS  Google Scholar 

  30. Chen, Y., and K.J. Wood. 2007. Interleukin-23 and TH17 cells in transplantation immunity: does 23+17 equal rejection? Transplantation 84:1071–1074.

    Article  PubMed  CAS  Google Scholar 

  31. van Maurik, A., K.J. Wood, and N. Jones. 2002. Cutting edge:CD4(+)CD25(+) alloantigen-specific immunoregulatory cells that can prevent CD8(+) T cell-mediated graft rejection: implications for anti-CD154 immunotherapy. J Immunol 169:5401–5404.

    PubMed  Google Scholar 

  32. Li, Y., T. Koshiba, A. Yoshizawa, Y. Yonekawa, K. Masuda, A. Ito, M. Ueda, T. Mori, H. Kawamoto, Y. Tanaka, S. Sakaguchi, N. Minato, K.J. Wood, and K. Tanaka. 2004. Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant 4:2118–2125.

    Article  PubMed  Google Scholar 

  33. Martinez-Llordella, M., I. Puig-Pey, G. Orlando, M. Ramoni, G. Tisone, A. Rimola, J. Lerut, D. Latinne, C. Margarit, I. Bilbao, S. Brouard, M. Hernandez-Fuentes, J.P. Soulillou, and A. Sanchez-Fueyo. 2007. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant 7:309–319.

    Article  PubMed  CAS  Google Scholar 

  34. Graca, L., S.P. Cobbold, and H. Waldmann. 2002. Identification of Regulatory T Cells in Tolerated Allografts. J Exp Med 195:1641–1646.

    Article  PubMed  CAS  Google Scholar 

  35. Mempel, T.R., M. Pittet, K. Khazaie, W. Weninger, R. Weissleder, H. Von Boehmer, and U.H. von Andrian. 2006. Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25:129–141.

    Article  PubMed  CAS  Google Scholar 

  36. Akl, A., N.D. Jones, N. Rogers, M.A. Bakr, A. Mostafa, E.L.M. El Shehawy, M.A. Ghoneim, and K.J. Wood. 2008. An investigation to assess the potential of CD25highCD4+ T cells to regulate responses to donor alloantigens in clinically stable renal transplant recipients. Transpl Int 21:65–73.

    Google Scholar 

  37. Frasca, L., C. Scotta, G. Lombardi, and E. Piccolella. 2002. Human anergic CD4+ T cells can act as suppressor cells by affecting autologous dendritic cell conditioning and survival. J Immunol 168:1060–1068.

    PubMed  CAS  Google Scholar 

  38. Vendetti, S., J.-G. Chai, J. Dyson, E. Simpson, G. Lombardi, and R. Lechler. 2000. Anergic T cell sinhibit the antigen presenting funciton of dendritic cells. J Immunol 165:1175–1181.

    PubMed  CAS  Google Scholar 

  39. Cederbom, L., H. Hall, and F. Ivars. 2000. CD4+CD25+ regulatory T cells down-regulate costimulatory molecules on antigen presenting cells. Eur J Immunol 30:1538–1543.

    Article  PubMed  CAS  Google Scholar 

  40. Tadokoro, C.E., G. Shakhar, S. Shen, Y. Ding, A.C. Lino, A. Maraver, J.J. Lafaille, and M.L. Dustin. 2006. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med 203:505–511.

    Article  PubMed  CAS  Google Scholar 

  41. Lin, C.-Y., L. Graca, S.P. Cobbold, and H. Waldmann. 2002. Dominant transplantation tolerance impairs CD8+ T cell function but not expansion. Nat Immunol 3:1208–1213.

    Article  PubMed  CAS  Google Scholar 

  42. Jones, N.D., M. Carvalho-Gaspar, S. Luo, M.O. Brook, L. Martin, and K.J. Wood. 2006. Effector and memory CD8+ T cells can be generated in response to alloantigen independently of CD4+ T cell help. J Immunol 176:2316–2323.

    PubMed  CAS  Google Scholar 

  43. Grossman, W., J. Verbsky, W. Barchet, M. Colonna, J. Atkinson, and T. Ley. 2004. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601.

    Article  PubMed  CAS  Google Scholar 

  44. Gondek, D.C., L.-F. Lu, S.A. Quezada, S. Sakaguchi, and R.J. Noelle. 2005. Cutting edge: Contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 174:1783–1786.

    PubMed  CAS  Google Scholar 

  45. Kreisel, D., A. Krupnick, A. Gelman, F. Engels, S. Popma, A. Krasinskas, K. Balsara, W. Szeto, L. Turka, and B. Rosengard. 2002. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med 8:233–239.

    Article  PubMed  CAS  Google Scholar 

  46. Choo, J., J. Seebach, V. Nickeleit, A. Shimizu, H. Lei, D. Sachs, and J. Madsen. 1997. Species differences in the expression of major histocompatibility complex class II antigens on coronary artery endothelium. Transplantation 64:1315–1322.

    Article  PubMed  CAS  Google Scholar 

  47. Thornton, A., and E.M. Shevach. 2000. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen non-specific. J Immunol 164:183–190.

    PubMed  CAS  Google Scholar 

  48. Karim, M., G. Feng, K.J. Wood, and A. Bushell. 2005. CD25+CD4+ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen specific reactivation in vivo is critical for bystander regulation. Blood 105:4871–4877.

    Article  PubMed  CAS  Google Scholar 

  49. Vukmanovic-Stejic, M., Y. Zhang, J. Cook, J. Fletcher, A. McQuaid, J. Maters, M.H. Rustin, L. Taams, P. Beverley, D. Macallan, and A.N. Akbar. 2006. Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 116:2423–2433.

    Article  PubMed  CAS  Google Scholar 

  50. Sawitzki, B., C.I. Kingsley, V. Oliveira, M. Karim, M. Herber, and K.J. Wood. 2005. Interferon gamma production by alloantigen reactive CD25+CD4+ regulatory T cells is important for their regulatory function in vivo. J Exp Med 201:1925–1935.

    Article  PubMed  CAS  Google Scholar 

  51. Sawitzki, B., A. Bushell, U. Steger, N. Jones, K. Risch, A. Siepert, M. Lehmann, I. Schmitt-Knosalla, K. Vogt, I. Gebuhr, K. Wood, and H.D. Volk. 2007. Identification of gene markers for the prediction of allograft rejection or permanent acceptance. Am J Transplant 7: 1091–1102.

    Article  PubMed  CAS  Google Scholar 

  52. Hassanain, H.C., SY, and S. Gupta. 1993. Differential regulation of human indoleamine 2,3-dioxygenase gene expression by interferons-γ and α:analysis of the regulatory region of the gene and identification of an interferon-γ inducible DNA binding factor. J Biol Chem 268:5077–5084.

    Google Scholar 

  53. Orabona, C., P. Puccetti, C. Vacca, S. Bicciato, A. Luchini, F. Fallorino, R. Bianchi, E. Velardi, K. Perrucio, A. Verlardi, V. Bronte, M. Fioretti, and U. Grohmann. 2006. Towards the identification of a tolerogenic signature of IDO competent dendritic cells. Blood 107:2846–2854.

    Article  PubMed  CAS  Google Scholar 

  54. Grohmann, U., C. Orabona, F. Fallorino, C. Vacca, F. Calcinaro, A. Falorni, P. Candeloro, M. Belladonna, R. Bianchi, M. Fioretti, and P. Puccetti. 2002. CTLA-4Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101.

    Article  PubMed  CAS  Google Scholar 

  55. Mellor, A., D. Keskin, T. Johnson, P. Chandler, and D. Munn. 2002. Cells expressing 2,3-dioxygenase inhibit T cell responses. J Immunol 168:3771–3776.

    PubMed  CAS  Google Scholar 

  56. Terness, P., T. Bauer, L. Rose, C. Dufter, A. Watzlik, H. Simon, and G. Opelz. 2002. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196: 447–457.

    Article  PubMed  CAS  Google Scholar 

  57. Beutelspacher, S., R. Pillai, M. Watson, P. Tan, J. Tsang, M. McClure, A. George, and D. Larkin. 2006. Function of indole-amine 2,3-dioxygensae in corneal allograft rejection and prolongation of allograft survival by over-expression. Eur J Immunol 36:690–700.

    Article  PubMed  CAS  Google Scholar 

  58. Billiau, A., H. Heremans, F. Vandekerckhove, R. Dijkmans, H. Sobis, E. Meulepas, and H. Carton. 1988. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J Immunol 140:1506–1510.

    PubMed  CAS  Google Scholar 

  59. Kelchtermans, H., B. De Klerck, T. Mitera, M. Van Balen, D. Bullens, A. Billiau, G. Leclercq, and P. Matthys. 2005. Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-gamma. Arthritis Res Ther 7:R402–R415.

    Article  PubMed  CAS  Google Scholar 

  60. Irmler, I.M., M. Gajda, and R. Brauer. 2007. Exacerbation of antigen-induced arthritis in IFN-{gamma}-deficient mice as a result of unrestricted IL-17 response. J Immunol 179:6228–6236.

    PubMed  CAS  Google Scholar 

  61. Wood, K.J., and B. Sawitzki. 2006. Interferon γ: a crucial role in the function of induced regulatory T cells in vivo. Trends in Immunology 27:183–187.

    Article  PubMed  CAS  Google Scholar 

  62. Konieczny, B., Z. Dai, E. Elwood, S. Saleem, P. Linsley, F. Baddoura, C. Larsen, T. Pearson, and F. Lakkis. 1998. IFN-g is critical for long-term allograft survival indcued by blocking the CD28 and CD40 ligand T cell costimulation pathways. J Immunol 160:2059–2064.

    PubMed  CAS  Google Scholar 

  63. Yu, X.-Z., M.H. Albert, P.J. Martin, and C. Anasetti. 2004. CD28 ligation induces transplantation tolerance by IFN-{gamma}_dependent depletion of T cells that recognize alloantigens. J Clin Invest 113:1624–1630.

    PubMed  CAS  Google Scholar 

  64. Saleem, S., B. Konieczny, R. Lowry, F. Baddoura, and F. Lakkis. 1996. Acute rejection of vascularized heart allografts in the absence of IFNγ. Transplantation 62:1908–1911.

    Article  PubMed  CAS  Google Scholar 

  65. Markees, T., N. Phillips, E. Gordon, R. Noelle, L. Shults, J. MOrdes, D. Greiner, and A. Rossini. 1998. Long term survival of skin allografts induced by donor splenocytes and anti-CD154 antibody in thymectomised mice requires CD4+ T cells, interferon-γ and CTLA-4. J Clin Invest 101:2446–2455.

    Article  PubMed  CAS  Google Scholar 

  66. O'Garra, A. 1998. Cytokines induce the development of functionally heterogenous T helper cell subsets. Immunity 8:275–283.

    Article  PubMed  Google Scholar 

  67. Gajewski, T.F., and F.W. Fitch. 1988. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN- gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol 140:4245–4252.

    PubMed  CAS  Google Scholar 

  68. Tewari, K., Y. Nakayama, and M. Suresh. 2007. Role of Direct Effects of IFN-{gamma} on T Cells in the Regulation of CD8 T Cell Homeostasis. J Immunol 179:2115–2125.

    PubMed  CAS  Google Scholar 

  69. Thompson, C., and J. Allison. 1997. The emerging role of CTLA-4 as an immune attenuator. Immunity 7:445–450.

    Article  PubMed  CAS  Google Scholar 

  70. Walunas, T., D. Lenschow, C. Bakker, P. Linsley, G. Freeman, J. Green, C. Thompson, and J. Bluestone. 1994. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413.

    Article  PubMed  CAS  Google Scholar 

  71. Waterhouse, P., J. Penninger, E. Timms, A. Wakeham, A. Shahinian, K. Lee, C. Thompson, H. Griesser, and T. Mak. 1995. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 270:985–988.

    Article  PubMed  CAS  Google Scholar 

  72. Takahashi, T., T. Tagami, S. Yamazaki, T. Uede, J. Shimuzu, N. Sakaguchi, T. Mak, and S. Sakaguchi. 2000. Immunologic self tolerance is maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte associated antigen 4. J Exp Med 192:303–310.

    Article  PubMed  CAS  Google Scholar 

  73. Read, S., V. Malmstrom, and F. Powrie. 2000. Cytotoxic T lymphocyte associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J Exp Med 192:295–302.

    Article  PubMed  CAS  Google Scholar 

  74. Azimzadeh, A.M., S. Pfeiffer, G. Wu, C. Schroder, G.L. Zorn, 3rd, S.S. Kelishadi, E. Ozkaynak, M. Kehry, J.B. Atkinson, G.G. Miller, and R.N. Pierson, 3rd. 2006. Alloimmunity in primate heart recipients with CD154 blockade: evidence for alternative costimulation mechanisms. Transplantation 81:255–264.

    Article  PubMed  CAS  Google Scholar 

  75. Fallarino, F., U. Grohmann, K. Hwang, C. Orabona, C. Vacca, R. Bianchi, M. Belladonna, M. Fioretti, M. Alegre, and P. Puccetti. 2003. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4:1206–12012.

    Article  PubMed  CAS  Google Scholar 

  76. Schneider, H., E. Valk, S. da Rocha, B. Wei, and C. Rudd. 2005. CTLA-4 upregulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternative basis for co-receptor function. Proc Natl Acad Sci USA 102:12861–12866.

    Article  PubMed  CAS  Google Scholar 

  77. Schneider, H., J. Downey, A. Smith, B.H. Zinselmeyer, C. Rush, J.M. Brewer, B. Wei, N. Hogg, P. Garside, and C.E. Rudd. 2006. Reversal of the TCR Stop Signal by CTLA-4. Science 313:1972–1975.

    Article  PubMed  CAS  Google Scholar 

  78. Li, L., R.J. Greenwald, E.M. Lafuente, D. Tzachanis, A. Berezovskaya, G.J. Freeman, A.H. Sharpe, and V.A. Boussiotis. 2005. Rap1-GTP is a negative regulator of Th cell function and promotes the generation of CD4+CD103+ regulatory T cells in vivo. J Immunol 175:3133–3139.

    PubMed  CAS  Google Scholar 

  79. Hernandez-Fuentes, M., A. Warrens, and R. Lechler. 2003. Immunological monitoring. Immunol Rev 196:247.

    Article  PubMed  CAS  Google Scholar 

  80. Soulillou, J.P. 2001. Immune monitoring for rejection of kidney transplants. N Engl J Med 344:1006.

    Article  PubMed  CAS  Google Scholar 

  81. Stordeur, P., L. Zhou, and M. Goldman. 2002. Analysis of spontaneous mRNA cytokine production in peripheral blood. J Immunol Methods 261:195.

    Article  PubMed  CAS  Google Scholar 

  82. Sarwal, M., M. Chua, and N. Kambham. 2003. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med 349:125.

    Article  PubMed  CAS  Google Scholar 

  83. Brouard, S., E. Mansfield, C. Braud, L. Li, M. Giral, S.-c. Hsieh, D. Baeten, M. Zhang, J. Ashton-Chess, C. Braudeau, F. Hsieh, A. Dupont, A. Pallier, A. Moreau, S. Louis, C. Ruiz, O. Salvatierra, J.-P. Soulillou, and M. Sarwal. 2007. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci 104:15448–15453.

    Article  PubMed  CAS  Google Scholar 

  84. Mueller, T.F., J. Reeve, G.S. Jhangri, M. Mengel, Z. Jacaj, L. Cairo, M. Obeidat, G. Todd, R. Moore, K.S. Famulski, J. Cruz, D. Wishart, C. Meng, B. Sis, K. Solez, B. Kaplan, and P.F. Halloran. 2008. The transcriptome of the implant biopsy identifies donor kidneys at increased risk of delayed graft function. Am J Transplant 8:78–85.

    PubMed  CAS  Google Scholar 

  85. Nickel, P., J. Lacha, and S. Ode-Hakim. 2001. Cytotoxic efector molecule gene expression in acute renal allograft rejection: correlation with clinical outcome; histopathology and function of the allograft. Transplantation 72:1158.

    Article  PubMed  CAS  Google Scholar 

  86. Sabek, O., M. Dorak, M. Kotb, A.O. Gaber, and L. Gaber. 2002. Quantitative detection of T-cell activation markers by real-time PCR in renal transplant rejection and correlation with histopathologic evaluation. Transplantation 74:701.

    Article  PubMed  CAS  Google Scholar 

  87. Shulzhenko, N., A. Morgun, and X. Zheng. 2001. Intragraft activation of genes encoding cytotoxic T lymphocyte effector molecules precedes the histological evidence of rejection in human cardiac transplantation. Transplantation 72:1705.

    Article  PubMed  CAS  Google Scholar 

  88. Strehlau, J., M. Pavlakis, M. Lipman, W. Maslinski, M. Shaprio, and T. Strom. 1996. The intragraft gene activation of markers reflecting T-cell-activation and -cytotoxicity analyzed by quantitative RT-PCR in renal transplantation. Clin Nephrol 46:30.

    PubMed  CAS  Google Scholar 

  89. Li, B., C. Hartono, and R. Ding. 2001. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 344:947.

    Article  PubMed  CAS  Google Scholar 

  90. Simon, T., G. Opelz, M. Wiesel, R. Ott, and C. Susal. 2003. Serial peripheral blood perforin and granzyme B gene expression measurements for prediction of acute rejection in kidney graft recipients. Am J Transplant 3:1121.

    Article  PubMed  CAS  Google Scholar 

  91. Saiura, A., C. Mataki, and T. Murakami. 2001. A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis. Transplantation 72:320.

    Article  PubMed  CAS  Google Scholar 

  92. Akalin, E., R. Hendrix, and R. Polavarapu. 2001. Gene expression analysis in human renal allograft biopsy samples using high-density oligoarray technology. Transplantation 72:948.

    Article  PubMed  CAS  Google Scholar 

  93. Flechner, S., S. Kurian, and S. Head. 2004. Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes. Am J Transplant 4:1475.

    Article  PubMed  Google Scholar 

  94. Scherer, A., A. Krause, J. Walker, A. Korn, D. Niese, and F. Raulf. 2003. Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies. Transplantation 75:1323.

    Article  PubMed  CAS  Google Scholar 

  95. Deng, M., H.J. Eisen, and M. Mehra. 2006. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant 6:150.

    Article  PubMed  CAS  Google Scholar 

  96. Hoffmann, S., D.A. Hale, and D. Kleiner. 2005. Functionally significant renal allograft rejection is defined by transcriptional criteria. Am J Transplant 5:573.

    Article  PubMed  CAS  Google Scholar 

  97. Kosuge, T., T. Tamura, H. Nariuchi, and S. Toyoshima. 2000. Effect of inhibitors of glycoprotein processing on cytokine secretion and production in anti-CD3 stimulated T cells. Biol Pharm Bull 23:1–5.

    Article  PubMed  CAS  Google Scholar 

  98. Demetriou, M., M. Granovsky, S. Quaggin, and J. Dennis. 2001. Negative regulation of T cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409:733–739.

    Article  PubMed  CAS  Google Scholar 

  99. Dennis, J., J. Pawling, P. Cheung, E. Partridge, and M. Demetriou. 2002. UDP-N-acetyl- glucosamine:alpha-6-D-mannoside beta1,6 N-acetylglucosaminyltransferase V (Mgat5) deficient mice. Biochem Biophys Acta 1573:414.

    Article  PubMed  CAS  Google Scholar 

  100. Morgan, R., G. Gao, J. Pawling, J. Dennis, M. Demetriou, and B. Li. 2004. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J Immunol 173:7200.

    PubMed  CAS  Google Scholar 

  101. Cobbold, S.P., K. Nolan, and L. Graca. 2003. Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms. Immunol Rev 196:109.

    Article  PubMed  CAS  Google Scholar 

  102. Zelenika, D., E. Adams, S. Humm, L. Graca, S. Thompson, S.P. Cobbold, and H. Waldmann. 2002. Regulatory T cells overexpress a subset of Th2 gene transpcripts. J Immunol 168:1069–1079.

    PubMed  CAS  Google Scholar 

  103. Matsui, Y., A. Saiura, and Y. Sugawara. 2003. Identification of gene expression profile in tolerizing murine cardiac allograft by costimulatory blockade. Physiol Genomics 15:199.

    PubMed  CAS  Google Scholar 

  104. Louvet, C., E. Chiffoleau, and M. Heslan. 2005. Identification of a new member of the CD20/FcepsilonRIbeta family overexpressed in tolerated allografts. Am J Transplant 5:2143.

    Article  PubMed  CAS  Google Scholar 

  105. Metcalfe, S., and D. SMPA. 2005. Transplantation tolerance: gene expression profiles comparing allotolerance vs. allorejection. Int Immunopharmacol 5:33.

    Article  PubMed  CAS  Google Scholar 

  106. Tan, J.T., B. Ernst, W.C. Kieper, E. LeRoy, J. Sprent, and C.D. Surh. 2002. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J Exp Med 195:1523–1532.

    Article  PubMed  CAS  Google Scholar 

  107. Murakami, M., A. Sakamoto, J. Bender, J. Kappler, and P. Marrack. 2002. CD25+CD4+ T cells contribute to the control of memory CD8+ T cells. Proc Natl Acad Sci 99:8832–8837.

    Article  PubMed  CAS  Google Scholar 

  108. Pearl, J.P., J. Parris, D.A. Hale, S.C. Hoffmann, W.B. Bernstein, K.L. McCoy, S.J. Swanson, R.B. Mannon, M. Roederer, and A.D. Kirk. 2005. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 5:465–474.

    Article  PubMed  CAS  Google Scholar 

  109. Trzonkowski, P., M. Zilvetti, P. Friend, and K.J. Wood. 2006. Recipient memory-like lymphocytes remain unresponsive to graft antigens after CAMPATH-1H induction with reduced maintenance immunosuppression. Transplantation 82:1342–1351.

    Article  PubMed  Google Scholar 

  110. Valujskikh, A., B. Pantenburg, and P.S. Heeger. 2002. Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am J Transplant 2:501–509.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Transplantation Research Immunology Group, Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK

    Kathryn J Wood

Authors
  1. Kathryn J Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew Bushell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manuela Carvalho-Gaspar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gang Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ross Francis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nick Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elaine Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shiqiao Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ian Lyons
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satish Nadig
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Birgit Sawitzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gregor Warnecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Bin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Joanna Więckiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathryn J Wood .

Editor information

Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2008 Springer Science+Business Media, LLC

    About this chapter

    Cite this chapter

    Wood, K.J. et al. (2008). Regulatory T Cells in Transplantation. In: Jiang, S. (eds) Regulatory T Cells and Clinical Application. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77909-6_16

    Download citation

    Publish with us

    Policies and ethics

    Search

    Navigation