Skip to main content

Advertisement

Log in

Clinical transplantation tolerance

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Transplantation is the treatment of choice for many if not most causes of end-stage organ failure. Over 20,000 organ transplant procedures were performed in the USA in 2009 to treat patients with failed or failing kidneys, livers, hearts, lungs, and intestines, and there remain 85,000 individuals waiting on the transplant list. Currently, in the USA, there are over 170,000 individuals living with a transplanted organ. Virtually, all of these individuals receive maintenance immunosuppression in an attempt to maximize the function and survival of the transplanted organ. However, it is clear that the long-term use of immunosuppressive agents is associated with an extensive list of undesirable side effects that have the potential to limit the survival of the patient and transplanted organ as well as to compromise quality of life. Although the ability to induce reproducibly a state of robust, stable tolerance would address this problem, tolerance remains an infrequent event in clinical transplantation that is largely a consequence of chance. Factors limiting the broader investigation of clinical transplantation tolerance include the lack of therapeutic regimens known to favor tolerance in humans, the lack of validated assays or biomarkers predictive of tolerance, and concerns about the safety and ethics of complete withdrawal of immunosuppression given the very good results achievable with current immunosuppression. Despite these barriers, a number of investigators have continued to conduct well-designed and carefully supervised studies with the long-term goal of making clinical transplantation tolerance more feasible. The aim of this review is to summarize the status of these studies.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Billingham RE, Brent L, Medawar PB (1953) "Actively acquired tolerance" of foreign cells. Nature 172:603–606

    Article  PubMed  CAS  Google Scholar 

  2. Owens ML, Maxwell JG, Goodnight J, Wolcott MW (1975) Discontinuance of immunosuppression in renal transplant patients. Arch Surg 110(12):1450–1451

    Article  PubMed  CAS  Google Scholar 

  3. Zoller KM, Cho SI, Cohen JJ, Harrington JT (1980) Cessation of immunosuppressive therapy after successful transplantation: a national survey. Kidney Int 18(1):110–114

    Article  PubMed  CAS  Google Scholar 

  4. Kingsley CI, Nadig SN, Wood KJ (2007) Transplantation tolerance: lessons from experimental rodent models. Transpl Int 20(10):828–841

    Article  PubMed  CAS  Google Scholar 

  5. Lerut J, Sanchez-Fueyo A (2006) An appraisal of tolerance in liver transplantation. Am J Transplant 6(8):1774–1780

    Article  PubMed  CAS  Google Scholar 

  6. Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noel C et al (2006) Clinical operational tolerance after kidney transplantation. Am J Transplant 6(4):736–746

    Article  PubMed  CAS  Google Scholar 

  7. Halloran PF, Bromberg J, Kaplan B, Vincenti F (2008) Tolerance versus immunosuppression: a perspective. Am J Transplant 8(7):1365–1366

    Article  PubMed  CAS  Google Scholar 

  8. Ballet C, Roussey-Kesler G, Aubin JT, Brouard S, Giral M, Miqueu P et al (2006) Humoral and cellular responses to influenza vaccination in human recipients naturally tolerant to a kidney allograft. Am J Transplant 6(11):2796–2801

    Article  PubMed  CAS  Google Scholar 

  9. Orlando G, Manzia T, Baiocchi L, Sanchez-Fueyo A, Angelico M, Tisone G (2008) The Tor Vergata weaning off immunosuppression protocol in stable HCV liver transplant patients: the updated follow up at 78 months. Transpl Immunol 20(1–2):43–47

    Article  PubMed  Google Scholar 

  10. Tzakis A, Tryphonopoulos P, Weppler D, Garcia-Morales R, Cirocco R, Sornaraz A et al (2008) Operational tolerance: long term observations after complete withdrawal of immunosuppression (ISP) in liver transplant recipients. Am J Transplant 8(Supplement 2):542

    Google Scholar 

  11. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J et al (1998) Prope tolerance, perioperative campath 1 H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 351(9117):1701–1702

    Article  PubMed  CAS  Google Scholar 

  12. Knechtle SJ, Pascual J, Bloom DD, Torrealba JR, Jankowska-Gan E, Burlingham WJ et al (2009) Early and limited use of tacrolimus to avoid rejection in an alemtuzumab and sirolimus regimen for kidney transplantation: clinical results and immune monitoring. Am J Transplant 9(5):1087–1098

    Article  PubMed  CAS  Google Scholar 

  13. Nikolich-Zugich J, Slifka MK, Messaoudi I (2004) The many important facets of T-cell repertoire diversity. Nat Rev Immunol 4(2):123–132

    Article  PubMed  CAS  Google Scholar 

  14. Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA (2001) Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 166(2):973–981

    PubMed  CAS  Google Scholar 

  15. Ford ML, Koehn BH, Wagener ME, Jiang W, Gangappa S, Pearson TC et al (2007) Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation. J Exp Med 204(2):299–309, Epub 2007 Jan 29

    Article  PubMed  CAS  Google Scholar 

  16. Valujskikh A, Pantenburg B, Heeger PS (2002) Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am J Transplant 2(6):501–509

    Article  PubMed  CAS  Google Scholar 

  17. Adams AB, Williams MA, Jones TR, Shirasugi N, Durham MM, Kaech SM et al (2003) Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 111(12):1887–1895

    PubMed  CAS  Google Scholar 

  18. Pantenburg B, Heinzel F, Das L, Heeger PS, Valujskikh A (2002) T cells primed by Leishmania major infection cross-react with alloantigens and alter the course of allograft rejection. J Immunol 169(7):3686–3693

    PubMed  CAS  Google Scholar 

  19. Welsh RM, Markees TG, Woda BA, Daniels KA, Brehm MA, Mordes JP et al (2000) Virus-induced abrogation of transplantation tolerance induced by donor-specific transfusion and anti-CD154 antibody. J Virol 74(5):2210–2218

    Article  PubMed  CAS  Google Scholar 

  20. Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL et al (2005) Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 5(3):465–474

    Article  PubMed  CAS  Google Scholar 

  21. Wu Z, Bensinger SJ, Zhang J, Chen C, Yuan X, Huang X et al (2004) Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med 10(1):87–92

    Article  PubMed  CAS  Google Scholar 

  22. Najafian N, Albin MJ, Newell KA (2006) How can we measure immunologic tolerance in humans? J Am Soc Nephrol 17(10):2652–2663, Epub 006 Aug 23

    Article  PubMed  CAS  Google Scholar 

  23. Newell KA, Larsen CP (2006) Tolerance assays: measuring the unknown. Transplantation 81(11):1503–1509

    Article  PubMed  Google Scholar 

  24. Marder BA, Schroppel B, Lin M, Schiano T, Parekh R, Tomer Y et al (2003) The impact of costimulatory molecule gene polymorphisms on clinical outcomes in liver transplantation. Am J Transplant 3(4):424–431

    Article  PubMed  CAS  Google Scholar 

  25. Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N et al (2003) Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. Am J Transplant 3(7):878–884

    Article  PubMed  CAS  Google Scholar 

  26. Lee PC, Zhu L, Terasaki PI, Everly MJ (2009) HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation 88(4):568–574

    Article  PubMed  CAS  Google Scholar 

  27. Flechner SM, Kurian SM, Head SR, Sharp SM, Whisenant TC, Zhang J et al (2004) Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes. Am J Transplant 4(9):1475–1489

    Article  PubMed  Google Scholar 

  28. Li B, Hartono C, Ding R, Sharma VK, Ramaswamy R, Qian B et al (2001) Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. N Engl J Med 344(13):947–954

    Article  PubMed  CAS  Google Scholar 

  29. Schaub S, Rush D, Wilkins J, Gibson IW, Weiler T, Sangster K et al (2004) Proteomic-based detection of urine proteins associated with acute renal allograft rejection. J Am Soc Nephrol 15(1):219–227

    Article  PubMed  CAS  Google Scholar 

  30. Gagne K, Brouard S, Giral M, Sebille F, Moreau A, Guillet M et al (2000) Highly altered V beta repertoire of T cells infiltrating long-term rejected kidney allografts. J Immunol 164(3):1553–1563

    PubMed  CAS  Google Scholar 

  31. Kowalski R, Post D, Schneider MC, Britz J, Thomas J, Deierhoi M et al (2003) Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant 17(2):77–88

    Article  PubMed  Google Scholar 

  32. Cortesini R, Renna-Molajoni E, Cinti P, Pretagostini R, Ho E, Rossi P et al (2002) Tailoring of immunosuppression in renal and liver allograft recipients displaying donor specific T-suppressor cells. Hum Immunol 63(11):1010–1018

    Article  PubMed  CAS  Google Scholar 

  33. Sykes M (2007) Immune tolerance: mechanisms and application in clinical transplantation. J Intern Med 262(3):288–310

    Article  PubMed  CAS  Google Scholar 

  34. Agarwal A, Shen LY, Kirk AD (2008) The role of alemtuzumab in facilitating maintenance immunosuppression minimization following solid organ transplantation. Transpl Immunol 20(1–2):6–11

    Article  PubMed  CAS  Google Scholar 

  35. Kirk AD, Hale DA, Mannon RB, Kleiner DE, Hoffmann SC, Kampen RL et al (2003) Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1 H). Transplantation 76(1):120–129

    Article  PubMed  CAS  Google Scholar 

  36. Li Y, Li XC, Zheng XX, Wells AD, Turka LA, Strom TB (1999) 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

    Article  PubMed  CAS  Google Scholar 

  37. Li Y, Zheng XX, Li XC, Zand MS, Strom TB (1998) Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 66(10):1387–1388

    Article  PubMed  CAS  Google Scholar 

  38. Thomson AW, Turnquist HR, Raimondi G (2009) Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9(5):324–337

    Article  PubMed  CAS  Google Scholar 

  39. Li XC, Rothstein DM, Sayegh MH (2009) Costimulatory pathways in transplantation: challenges and new developments. Immunol Rev 229(1):271–293

    Article  PubMed  CAS  Google Scholar 

  40. Larsen CP, Elwood ET, Alexander DZ, Ritchie SC, Hendrix R, Tucker-Burden C et al (1996) Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381(6581):434–438

    Article  PubMed  CAS  Google Scholar 

  41. Kirk AD, Harlan DM, Armstrong NN, Davis TA, Dong Y, Gray GS et al (1997) CTLA4Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 94:8789–8794

    Article  PubMed  CAS  Google Scholar 

  42. Kenyon NS, Chatzipetrou M, Masetti M, Ranuncoli A, Oliveira M, Wagner JL et al (1999) Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci U S A 96(14):8132–8137

    Article  PubMed  CAS  Google Scholar 

  43. Larsen CP, Pearson TC, Adams AB, Tso P, Shirasugi N, Strobertm E et al (2005) Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 5(3):443–453

    Article  PubMed  CAS  Google Scholar 

  44. Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G et al (2005) Costimulation blockade with belatacept in renal transplantation. N Engl J Med 353(8):770–781

    Article  PubMed  CAS  Google Scholar 

  45. Weaver TA, Charafeddine AH, Agarwal A, Turner AP, Russell M, Leopardi FV et al (2009) Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med 15(7):746–749

    Article  PubMed  CAS  Google Scholar 

  46. Sykes M (2009) Hematopoietic cell transplantation for tolerance induction: animal models to clinical trials. Transplantation 87(3):309–316

    Article  PubMed  Google Scholar 

  47. Wekerle T, Sayegh MH, Hill J, Zhao Y, Chandraker A, Swenson KG et al (1998) Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J Exp Med 187(12):2037–2044

    Article  PubMed  CAS  Google Scholar 

  48. Kawai T, Cosimi AB, Colvin RB, Powelson J, Eason J, Kozlowski T et al (1995) Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation 59(2):256–262

    PubMed  CAS  Google Scholar 

  49. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL et al (2008) HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358(4):353–361

    Article  PubMed  CAS  Google Scholar 

  50. Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA et al (2008) Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med 358(4):362–368

    Article  PubMed  CAS  Google Scholar 

  51. Jones ND, Turvey SE, Van Maurik A, Hara M, Kingsley CI, Smith CH et al (2001) Differential susceptibility of heart, skin, and islet allografts to T cell-mediated rejection. J Immunol 166(4):2824–2830

    PubMed  CAS  Google Scholar 

  52. Zhang Z, Zhu L, Quan D, Garcia B, Ozcay N, Duff J et al (1996) Pattern of liver, kidney, heart, and intestine allograft rejection in different mouse strain combinations. Transplantation 62:1267–1272

    Article  PubMed  CAS  Google Scholar 

  53. Lozano JJ, Pallier A, Martinez-Llordella M, Lopez M, Soulillou JP, Brouard S et al (2010) Absence of significant overlap in blood transcriptional patterns between operationally tolerant liver and kidney recipients. Am J Transplant 10(Supplement 4):193

    Google Scholar 

  54. Mazariegos GV, Sindhi R, Thomson AW, Marcos A (2007) Clinical tolerance following liver transplantation: long term results and future prospects. Transpl Immunol 17(2):114–119

    Article  PubMed  Google Scholar 

  55. Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W et al (1997) Weaning of immunosuppression in liver transplant recipients. Transplantation 63(2):243–249

    Article  PubMed  CAS  Google Scholar 

  56. Koshiba T, Li Y, Takemura M, Wu Y, Sakaguchi S, Minato N et al (2007) Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol 17(2):94–97

    Article  PubMed  CAS  Google Scholar 

  57. Yoshitomi M, Koshiba T, Haga H, Li Y, Zhao X, Cheng D et al (2009) Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation 87(4):606–614

    Article  PubMed  Google Scholar 

  58. Tryphonopoulos P, Tzakis AG, Weppler D, Garcia-Morales R, Kato T, Madariaga JR et al (2005) The role of donor bone marrow infusions in withdrawal of immunosuppression in adult liver allotransplantation. Am J Transplant 5(3):608–613

    Article  PubMed  Google Scholar 

  59. Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A et al (2007) Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant 7(2):309–319

    Article  PubMed  CAS  Google Scholar 

  60. Martinez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J et al (2008) Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest 118(8):2845–2857

    PubMed  CAS  Google Scholar 

  61. Puig-Pey I, Bohne F, Benitez C, Lopez M, Martinez-Llordella M, Oppenheimer F et al (2010) Characterization of gammadelta T cell subsets in organ transplantation. Transpl Int 23(10):1045–1055

    Article  PubMed  CAS  Google Scholar 

  62. Millan O, Benitez C, Guillen D, Lopez A, Rimola A, Sanchez-Fueyo A et al (2010) Biomarkers of immunoregulatory status in stable liver transplant recipients undergoing weaning of immunosuppressive therapy. Clin Immunol 137(3):337–346

    Article  PubMed  CAS  Google Scholar 

  63. Seyfert-Margolis V, Feng S (2010) Tolerance: is it achievable in pediatric solid organ transplantation? Pediatr Clin North Am 57(2):523–538

    Article  PubMed  Google Scholar 

  64. Starzl TE, Demetris AJ, Trucco M (1993) Chimerism and donor specific nonreactivity 27 to 29 years after kidney allotransplantation. Transplantation 55:1272–1277

    Article  PubMed  CAS  Google Scholar 

  65. VanBuskirk AM, Burlingham WJ, Jankowska-Gan E, Chin T, Kusaka S, Geissler F et al (2000) Human allograft acceptance is associated with immune regulation. J Clin Invest 106(1):145–155

    Article  PubMed  CAS  Google Scholar 

  66. Brouard S, Dupont A, Giral M, Louis S, Lair D, Braudeau C et al (2005) Operationally tolerant and minimally immunosuppressed kidney recipients display strongly altered blood T-cell clonal regulation. Am J Transplant 5(2):330–340

    Article  PubMed  Google Scholar 

  67. Baeten D, Louis S, Braud C, Braudeau C, Ballet C, Moizant F et al (2006) Phenotypically and functionally distinct CD8+ lymphocyte populations in long-term drug-free tolerance and chronic rejection in human kidney graft recipients. J Am Soc Nephrol 17(1):294–304, Epub 2005 Dec 7

    Article  PubMed  CAS  Google Scholar 

  68. Louis S, Braudeau C, Giral M, Dupont A, Moizant F, Robillard N et al (2006) Contrasting CD25hiCD4 + T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation 81(3):398–407

    Article  PubMed  Google Scholar 

  69. Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC et al (2007) Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci U S A 104(39):15448–15453, Epub 2007 Sep 14

    Article  PubMed  CAS  Google Scholar 

  70. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M et al (2010) Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest 120(6):1836–1847

    Article  PubMed  CAS  Google Scholar 

  71. Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P et al (2010) Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest 120(6):1848–1861

    Article  PubMed  CAS  Google Scholar 

  72. Liu C, Noorchashm H, Sutter JA, Naji M, Prak EL, Boyer J et al (2007) B lymphocyte-directed immunotherapy promotes long-term islet allograft survival in nonhuman primates. Nat Med 13(11):1295–1298

    Article  PubMed  CAS  Google Scholar 

  73. Lund FE, Randall TD (2010) Effector and regulatory B cells: modulators of CD4(+) T cell immunity. Nat Rev Immunol 10(4):236–247

    Article  PubMed  CAS  Google Scholar 

  74. Pallier A, Hillion S, Danger R, Giral M, Racape M, Degauque N et al (2010) Patients with drug-free long-term graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. Kidney Int 78(5):503–513

    Article  PubMed  CAS  Google Scholar 

  75. Fudaba Y, Spitzer TR, Shaffer J, Kawai T, Fehr T, Delmonico F et al (2006) Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses. Am J Transplant 6(9):2121–2133, Epub 006 Jun 22

    Article  PubMed  CAS  Google Scholar 

  76. Mazariegos GV, Zahorchak AF, Reyes J, Chapman H, Zeevi A, Thomson AW (2005) Dendritic cell subset ratio in tolerant, weaning and non-tolerant liver recipients is not affected by extent of immunosuppression. Am J Transplant 5(2):314–322

    Article  PubMed  Google Scholar 

  77. Li Y, Koshiba T, Yoshizawa A, Yonekawa Y, Masuda K, Ito A et al (2004) Analyses of peripheral blood mononuclear cells in operational tolerance after pediatric living donor liver transplantation. Am J Transplant 4(12):2118–2125

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenneth A. Newell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Newell, K.A. Clinical transplantation tolerance. Semin Immunopathol 33, 91–104 (2011). https://doi.org/10.1007/s00281-011-0255-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-011-0255-y

Keywords

Navigation