Tolerance in clinical transplantation: progress, challenge or just a dream?

Review Article

Abstract

Introduction

The achievement of clinical operational tolerance (COT) is still considered a major goal in the academic field of solid organ transplantation. Even COT is feasible and safe in selected cases after liver transplantation, in the clinical arena of solid organ transplantation, tolerance remains, for the most part, a concept rather than a reality.

Challenges

Although modern immunosuppression regimens have effectively handled acute rejection, nearly all organs except the liver commonly suffer chronic immunologic damage that impairs organ function, threatening patient and allograft survival. Strong arguments in favour of conducting clinical tolerance trials are the high number of grafts still lost due to chronic rejection, the burden of serious adverse effects from immunosuppressants which causes considerable cardiovascular morbidity and mortality, respectively, and the fact that sporadic tolerance can be observed in rare cases where non-adherence to immunosuppressive regimens is linked with a state of long-lasting organ tolerance. Whereas molecule-based regimens have been largely ineffective, cell-based tolerance protocols have delivered some encouraging results to achieve COT.

Discussion

In combination with donor bone marrow-derived stem cells, some encouraging results in COT development were reported lately for renal transplantation as well. However, less toxic conditioning protocols and more experience by use of cell products with regulatory properties in combination with synergizing immunosuppressive drugs is required to launch future tolerance trials for a broader spectrum of potential transplant candidates. New methods in immunomonitoring including biomarkers, microarray-based genetic tolerance signatures and functional assays may pave the way to achieve COT in upcoming clinical trials.

Keywords

Clinical operational tolerance Solid organ transplantation Tolerance Organ tolerance Stem cell Immune regulation Regulatory cell 

References

  1. 1.
    Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B (2004) Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 4(3):378–383PubMedGoogle Scholar
  2. 2.
    Lerut J, Bonaccorsi-Riani E, Finet P, Gianello P (2009) Minimization of steroids in liver transplantation. Transpl Int 22(1):2–19PubMedGoogle Scholar
  3. 3.
    Demetris AJ, Lunz JG, Randhawa P, Wu T, Nalesnik M, Thomson AW (2009) Monitoring of human liver and kidney allograft tolerance: a tissue/histopathology perspective. Transpl Int 22(1):120–141PubMedGoogle Scholar
  4. 4.
    Orlando G, Soker S, Wood K (2009) Operational tolerance after liver transplantation. J Hepatol 50(6):1247–1257PubMedGoogle Scholar
  5. 5.
    Orlando G, Hematti P, Stratta RJ, Burke GW, Di Cocco P, Pisani F, Soker S, Wood K (2010) Clinical operational tolerance after renal transplantation current status and future challenges. Ann Surg 252(6):915–928PubMedGoogle Scholar
  6. 6.
    Svendsen UG, Aggestrup S, Heilmann C, Jacobsen N, Koch C, Larsen B, Svejgaard A, Thisted B, Petterson G (1995) Transplantation of a lobe of lung from mother-to-child following previous transplantation with maternal bone-marrow. Eur Respir J 8(2):334–337PubMedGoogle Scholar
  7. 7.
    Comerci GD, Williams TM, Kellie S (2009) Immune tolerance after total lymphoid irradiation for heart transplantation: immunosuppressant-free survival for 8 years. J Heart Lung Transplant 28(7):743–745PubMedGoogle Scholar
  8. 8.
    Weil R, Starzl TE, Porter KA, Kershaw M, Schroter GPJ, Koep LJ (1980) Renal isotransplantation without immunosuppression. Ann Surg 192(1):108–110PubMedGoogle Scholar
  9. 9.
    Burlingham WJ, Grailer AP, Fechner JH, Kusaka S, Trucco M, Kocova M, Belzer FO, Sollinger HW (1995) Microchimerism linked to cytotoxic T-lymphocyte functional unresponsiveness (clonal anergy) in a tolerant renal-transplant recipient. Transplantation 59(8):1147–1155PubMedGoogle Scholar
  10. 10.
    Trivedi HL, Mishra VV, Vanikar AV, Modi PR, Shah VR, Shah PR, Firoz A (2006) Embryonic stem cell derived and adult hematopoietic stem cell transplantation for tolerance induction in a renal allograft recipient: a case report. Transplant Proc 38(9):3103–3108PubMedGoogle Scholar
  11. 11.
    Burke GW, Ciancio G, Cirocco R, Markou M, Coker D, Roth D, Nery J, Esquenazi V, Miller J (1996) Association of interleukin-10 with rejection-sparing effect in septic kidney transplant recipients. Transplantation 61(7):1114–1116PubMedGoogle Scholar
  12. 12.
    Owens ML, Maxwell JG, Goodnight J, Wolcott MW (1975) Discontinuance of immunosuppression in renal-transplant patients. Arch Surg 110(12):1450–1451PubMedGoogle Scholar
  13. 13.
    Zoller KM, Cho SI, Cohen JJ, Harrington JT (1980) Cessation of immunosuppressive therapy after successful transplantation—a national survey. Kid Int 18(1):110–114Google Scholar
  14. 14.
    VanBuskirk AM, Burlingham WJ, Jankowska-Gan E, Chin T, Kusaka S, Geissler F, Pelletier RP, Orosz CG (2000) Human allograft acceptance is associated with immune regulation. J Clin Invest 106(1):145–155PubMedGoogle Scholar
  15. 15.
    Xu Q, Lee J, Jankowska-Gan E, Schultz J, Roennburg DA, Haynes LD, Kusaka S, Sollinger HW, Knechtle SJ, VanBuskirk AM, Torrealba JR, Burlingham WJ (2007) Human CD4(+)CD25(low) adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance. (vol 178, pg 3983, 2007). J Immunol 178(11):7488Google Scholar
  16. 16.
    Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noel C, Pillebout E, Brouard S, Soulillou JP (2006) Clinical operational tolerance after kidney transplantation. Am J Transplant 6(4):736–746PubMedGoogle Scholar
  17. 17.
    Baeten D, Louis S, Braud C, Braudeau C, Ballet C, Moizant F, Pallier A, Giral M, Brouard S, Soulillou JP (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):294–304PubMedGoogle Scholar
  18. 18.
    Brouard S, Mansfield E, Braud C, Li L, Giral M, Hsieh SC, Baeten D, Zhang M, Ashton-Chess J, Braudeau C, Hsieh F, Dupont A, Pallier A, Moreau A, Louis S, Ruiz C, Salvatierra O, Soulillou JP, Sarwal M (2007) Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc Natl Acad Sci USA 104(39):15448–15453PubMedGoogle Scholar
  19. 19.
    Burlingham WJ, Jankowska-Gan E, VanBuskirk A, Orosz CG, Lee JH, Kusaka S (2000) Loss of tolerance to a maternal kidney transplant is selective for HLA class II: evidence from trans-vivo DTH and alloantibody analysis. Hum Immunol 61(12):1395–1402PubMedGoogle Scholar
  20. 20.
    Billingham RE, Brent L, Medawar PB (1953) Actively acquired tolerance of foreign cells. Nature 172(4379):603–606PubMedGoogle Scholar
  21. 21.
    Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, McMichael J, Fung JJ, Starzl TE (1997) Weaning of immunosuppression in liver transplant recipients. Transplantation 63(2):243–249PubMedGoogle Scholar
  22. 22.
    Assy N, Adams PC, Myers P, Simon V, Minuk GY, Wall W, Ghent CN (2007) Randomized controlled trial of total immunosuppression withdrawal in liver transplant recipients: role of ursodeoxycholic acid. Transplantation 83(12):1571–1576PubMedGoogle Scholar
  23. 23.
    Devlin J, Doherty D, Thomson L, Wong T, Donaldson P, Portmann B, Williams R (1998) Defining the outcome of immunosuppression withdrawal after liver transplantation. Hepatology 27(4):926–933PubMedGoogle Scholar
  24. 24.
    Eason JD, Cohen AJ, Nair S, Alcantera T, Loss GE (2005) Tolerance: is it worth the risk? Transplantation 79(9):1157–1159PubMedGoogle Scholar
  25. 25.
    Girlanda R, Rela M, Williams R, O’Grady JG, Heaton ND (2005) Long-term outcome of immunosuppression withdrawal after liver transplantation. Transplant Proc 37(4):1708–1709PubMedGoogle Scholar
  26. 26.
    Pons JA, Yelamos J, Ramirez P, Oliver-Bonet M, Sanchez A, Rodriguez-Gago M, Navarro J, Bermejo J, Robles R, Parrilla P (2003) Endothelial cell chimerism does not influence allograft tolerance in liver transplant patients after withdrawal of immunosuppression. Transplantation 75(7):1045–1047PubMedGoogle Scholar
  27. 27.
    Takatsuki M, Uemoto S, Inomata Y, Sakamoto S, Hayashi M, Ueda M, Kanematsu T, Tanaka K (2001) Analysis of alloreactivity and intragraft cytokine profiles in living donor liver transplant recipients with graft acceptance. Transpl Immunol 8(4):279–286PubMedGoogle Scholar
  28. 28.
    Tisone G, Orlando G, Cardillo A, Palmieri G, Manzia TM, Baiocchi L, Lionetti R, Anselmo A, Toti L, Angelico M (2006) Complete weaning off immunosuppression in HCV liver transplant recipients is feasible and favourably impacts on the progression of disease recurrence. J Hepatol 44(4):702–709PubMedGoogle Scholar
  29. 29.
    Tryphonopoulos P, Tzakis AG, Weppler D, Garcia-Morales R, Kato T, Madariaga JR, Levi DM, Nishida S, Moon J, Selvaggi G, Regev A, Nery C, Bejarano P, Khaled A, Kleiner G, Esquenazi V, Miller J, Ruiz P, Ricordi C (2005) The role of donor bone marrow infusions in withdrawal of immunosuppression in adult liver allotransplantation. Am J Transplant 5(3):608–613PubMedGoogle Scholar
  30. 30.
    Feng S, Ekong U, Lobritto S, Demetris A, Rosenthal P, Alonso E, Tchao N (2009) ITN029ST: immunosuppression withdrawal in pediatric recipients of parental living donor liver transplants: preliminary results of a pilot study. Am J Transplant 9:244–245Google Scholar
  31. 31.
    Benitez C, Lozano JJ, Martinez-Llordella M, Puig-Pey I, Lopez M, Rodriguez A, Tisone G, Pirenne J, Lerut J, Sanchez-Fueyo A (2009) Use of transcriptional biomarkers to identify liver transplant recipients who can successfully discontinue immunosuppressive therapy. Am J Transplant 9:252Google Scholar
  32. 32.
    Lerut J, Sanchez-Fueyo A (2006) An appraisal of tolerance in liver transplantation. Am J Transplant 6(8):1774–1780PubMedGoogle Scholar
  33. 33.
    Starzl TE, Murase N, Abu-Elmagd K, Gray EA, Shapiro R, Eghtesad B, Corry RJ, Jordan ML, Fontes P, Gayowski T, Bond G, Scantlebury VP, Potdar S, Randhawa P, Wu T, Zeevi A, Nalesnik MA, Woodward J, Marcos A, Trucco M, Demetris AJ, Fung JJ (2003) Tolerogenic immunosuppression for organ transplantation. Lancet 361(9368):1502–1510PubMedGoogle Scholar
  34. 34.
    Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, Bradley J, Smith K, Waldmann H (1998) Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 351(9117):1701–1702PubMedGoogle Scholar
  35. 35.
    Kirk AD, Mannon RB, Kleiner DE, Swanson JS, Kampen RL, Cendales LK, Elster EA, Wakefield T, Chamberlain C, Hoffmann SC, Hale DA (2005) Results from a human renal allograft tolerance trial evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin. Transplantation 80(8):1051–1059PubMedGoogle Scholar
  36. 36.
    Trzonkowski P, Zilvetti M, Chapman S, Wieckiewicz J, Sutherland A, Friend P, Wood KJ (2008) Homeostatic repopulation by CD28(−)CD8(+) T cells in alemtuzumab-depleted kidney transplant recipients treated with reduced immunosuppression. Am J Transplant 8(2):338–347PubMedGoogle Scholar
  37. 37.
    Clatworthy MR, Friend PJ, Calne RY, Rebello PRU, Hale G, Waldmann H, Watson CJE (2009) Alemtuzumab (CAMPATH-1H) for the treatment of acute rejection in kidney transplant recipients: long-term follow-up. Transplantation 87(7):1092–1095PubMedGoogle Scholar
  38. 38.
    Ciancio G, Burke GW (2008) Alemtuzumab (Campath-1H) in kidney transplantation. Am J Transplant 8(1):15–20PubMedGoogle Scholar
  39. 39.
    Wu ZH, Bensinger SJ, Zhang JD, Chen CQ, Yuan XL, Huang XL, Markmann JF, Kassaee A, Rosengard BR, Hancock WW, Sayegh MH, Turka LA (2004) Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med 10(1):87–92PubMedGoogle Scholar
  40. 40.
    Sayegh MH, Fine NA, Smith JL, Rennke HG, Milford EL, Tilney NL (1991) Immunological-tolerance to renal-allografts after bone-marrow transplants from the same donors. Ann Int Med 114(11):954–955PubMedGoogle Scholar
  41. 41.
    Ernst B, Lee DS, Chang JM, Sprent J, Surh CD (1999) The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11(2):173–181PubMedGoogle Scholar
  42. 42.
    Goldrath AW, Bevan MJ (1999) Low-affinity ligands for the TCR drive proliferation of mature CD8(+) T cells in lymphopenic hosts. Immunity 11(2):183–190PubMedGoogle Scholar
  43. 43.
    Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, Mccoy KL, Swanson SJ, Mannon RB, Roederer M, Kirk AD (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):465–474PubMedGoogle Scholar
  44. 44.
    Trzonkowski P, Zilvetti M, Friend P, Wood KJ (2006) Recipient memory-like lymphocytes remain unresponsive to graft antigens after CAMPATH-1H induction with reduced maintenance immunosuppression. Transplantation 82(10):1342–1351PubMedGoogle Scholar
  45. 45.
    Helg C, Chapuis B, Bolle JF, Morel P, Salomon D, Roux E, Antonioli V, Jeannet M, Leski M (1994) Renal-transplantation without immunosuppression in a host with tolerance induced by allogeneic bone-marrow transplantation. Transplantation 58(12):1420–1422PubMedGoogle Scholar
  46. 46.
    Jacobsen N, Taaning E, Ladefoged J, Kristensen JK, Pedersen FK (1994) Tolerance to an Hla-B, Dr disparate kidney allograft after bone-marrow transplantation from same donor. Lancet 343(8900):800PubMedGoogle Scholar
  47. 47.
    Butcher JA, Hariharan S, Adams MB, Johnson CP, Roza AM, Cohen EP (1999) Renal transplantation for end-stage renal disease following bone marrow transplantation: a report of six cases, with and without immunosuppression. Clin Transplant 13(4):330–335PubMedGoogle Scholar
  48. 48.
    Sorof JM, Koerper MA, Portale AA, Potter D, Desantes K, Cowan M (1995) Renal-transplantation without chronic immunosuppression after T-cell-depleted, Hla-mismatched bone-marrow transplantation. Transplantation 59(11):1633–1635PubMedGoogle Scholar
  49. 49.
    Sellers MT, Deierhoi MH, Curtis JJ, Gaston RS, Julian BA, Lanier DC, Diethelm AG (2001) Tolerance in renal transplantation after allogeneic bone marrow transplantation—6-year follow-up. Transplantation 71(11):1681–1683PubMedGoogle Scholar
  50. 50.
    Buhler LH, Spitzer TR, Sykes M, Sachs DH, Delmonico FL, Tolkoff-Rubin N, Saidman SL, Sackstein R, McAfee S, Dey B, Colby C, Cosimi AB (2002) Induction of kidney allograft tolerance after transient lymphohematopoietic chimerism in patients with multiple myeloma and end-stage renal disease. Transplantation 74(10):1405–1409PubMedGoogle Scholar
  51. 51.
    Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, Shaffer J, Preffer FI, Ding RC, Sharma V, Fishman JA, Dey B, Ko DSC, Hertl M, Goes NB, Wong WC, Williams WW, Colvin RB, Sykes M, Sachs DH (2008) Brief report: HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med 358(4):353–361PubMedGoogle Scholar
  52. 52.
    Porcheray F, Wong W, Saidman SL, De Vito J, Girouard TC, Chittenden M, Shaffer J, Tolkoff-Rubin N, Dey BR, Spitzer TR, Colvin RB, Cosimi AB, Kawai T, Sachs DH, Sykes M, Zorn E (2009) B-cell immunity in the context of T-cell tolerance after combined kidney and bone marrow transplantation in humans. Am J Transplant 9(9):2126–2135PubMedGoogle Scholar
  53. 53.
    Bloom D, Chang Z, Pauly K, Kwun J, Fechner J, Hayes C, Samaniego M, Knechtle S (2009) BAFF is increased in renal transplant patients following treatment with alemtuzumab. Am J Transplant 9(8):1835–1845PubMedGoogle Scholar
  54. 54.
    Millan TLT, Shizuru JA, Hoffmann P, Dejbakhsh-Jones S, Scandling JD, Grumet FC, Tan JC, Salvatierra O, Hoppe RT, Strober S (2002) Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation. Transplantation 73(9):1386–1391PubMedGoogle Scholar
  55. 55.
    Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, Hoppe RT, Lowsky R, Engleman EG, Strober S (2008) Brief report: tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med 358(4):362–368PubMedGoogle Scholar
  56. 56.
    Owen RD (1945) Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102(2651):400–401PubMedGoogle Scholar
  57. 57.
    Newton WT, Anderson CB (1973) Planned preimmunization of renal-allograft recipients. Surgery 74(3):430–436PubMedGoogle Scholar
  58. 58.
    Burlingham WJ (1996) Chimerism after organ transplantation: is there any clinical significance? Clin Transplant 10(1):110–117PubMedGoogle Scholar
  59. 59.
    Schiopu A, Wood KJ (2008) Regulatory T cells: hypes and limitations. Curr Opin Organ Transplant 13(4):333–338PubMedGoogle Scholar
  60. 60.
    Sagoo P, Lombardi G, Lechler RI (2008) Regulatory T cells as therapeutic cells. Curr Opin Organ Transplant 13(6):645–653PubMedGoogle Scholar
  61. 61.
    Demirkiran A, Kok A, Kwekkeboom J, Kusters JG, Metselaar HJ, Tilanus HW, van der Laan LJW (2006) Low circulating regulatory T-cell levels after acute rejection in liver transplantation. Liver Transplant 12(2):277–284Google Scholar
  62. 62.
    Bestard O, Cruzado JM, Rama I, Torras J, Goma M, Seron D, Moreso F, Gil-Vernet S, Grinyo JM (2008) Presence of FoxP3(+) regulatory T cells predicts outcome of subclinical rejection of renal allografts. J Am Soc Nephrol 119(10):2020–2026Google Scholar
  63. 63.
    Meloni F, Vitulo P, Bunco AM, Paschetto E, Morosini M, Cascina A, Mazzucchelli I, Ciardelli L, Ogglonni T, Fietta AM, Pozzi E, Vigano M (2004) Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation 77(5):762–766PubMedGoogle Scholar
  64. 64.
    Radhakrishnan S, Cabrera R, Schenk EL, Nava-Parada P, Bell MP, Van Keulen VP, Marler RJ, Felts SJ, Pease LR (2010) Reprogrammed FoxP3(+) T regulatory cells become IL-17(+) antigen-specific autoimmune effectors in vitro and in vivo (Retraction of vol 181, pg 3137, 2008). J Immunol 184(11):6556Google Scholar
  65. 65.
    Afzali B, Mitchell P, Lechler RI, John S, Lombardi G (2010) Translational mini-review series on Th17 cells: induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 159(2):120–130PubMedGoogle Scholar
  66. 66.
    Koenen HJPM, Smeets RL, Vink PM, van Rijssen E, Boots AMH, Joosten I (2008) Human CD25(high)Foxp3(pos) regulatory T cells differentiate into IL-17-producing cells. Blood 112(6):2340–2352PubMedGoogle Scholar
  67. 67.
    Wang J, Huizinga TWJ, Toes REM (2009) De novo generation and enhanced suppression of human CD4(+)CD25(+) regulatory T cells by retinoic acid. J Immunol 183(6):4119–4126PubMedGoogle Scholar
  68. 68.
    Mitchell P, Afzali B, Lombardi G, Lechler RI (2009) The T helper 17-regulatory T cell axis in transplant rejection and tolerance. Curr Opin Organ Transplant 14(4):326–331PubMedGoogle Scholar
  69. 69.
    Hanson SE, Bentz ML, Hematti P (2010) Mesenchymal stem cell therapy for nonhealing cutaneous wounds. Plast Reconstr Surg 125(2):510–516PubMedGoogle Scholar
  70. 70.
    Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363(9419):1439–1441PubMedGoogle Scholar
  71. 71.
    Le Blanc K, Ringden O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Int Med 262(5):509–525Google Scholar
  72. 72.
    Le Blanc K, Pittenger MF (2005) Mesenchymal stem cells: progress toward promise. Cytotherapy 7(1):36–45PubMedGoogle Scholar
  73. 73.
    Crop M, Baan C, Weimar W, Hoogduijn M (2009) Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation. Transpl Int 22(4):365–376PubMedGoogle Scholar
  74. 74.
    Pulendran B (2009) Modulating vaccine responses with innate immunity. Cytokine 48(1–2):5Google Scholar
  75. 75.
    Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Ann Rev of Immunol 21:685–711Google Scholar
  76. 76.
    Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (2008) Foxp3(+) natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA 105(29):10113–10118PubMedGoogle Scholar
  77. 77.
    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3(+) regulatory T cell function. Science 322(5899):271–275PubMedGoogle Scholar
  78. 78.
    Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC, Pulendran B (2010) Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329(5993):849–853PubMedGoogle Scholar
  79. 79.
    Reichardt W, Durr C, von Elverfeldt D, Juttner E, Gerlach UV, Yamada M, Smith B, Negrin RS, Zeiser R (2008) Impact of mammalian target of rapamycin inhibition on lymphoid homing and tolerogenic function of nanoparticle-labeled dendritic cells following allogeneic hematopoietic cell transplantation. J Immunol 181(7):4770–4779PubMedGoogle Scholar
  80. 80.
    Stax AM, Gelderman KA, Schlagwein N, Essers MC, Kamerling SWA, Woltman AM, van Kooten C (2008) Induction of donor-specific T-cell hyporesponsiveness using dexamethasone-treated dendritic cells in two fully mismatched rat kidney transplantation models. Transplantation 86(9):1275–1282PubMedGoogle Scholar
  81. 81.
    Zhang XS, Li M, Lian DM, Zheng XF, Zhang ZX, Ichim TE, Xia XP, Huang XY, Vladau C, Suzuki M, Garcia B, Jevnikar AM, Min WP (2008) Generation of therapeutic dendritic cells and regulatory T cells for preventing allogeneic cardiac graft rejection. Clin Immunol 127(3):313–321PubMedGoogle Scholar
  82. 82.
    Reddy P, Sun YP, Toubai T, Duran-Struuck R, Clouthier SG, Weisiger E, Maeda Y, Tawara I, Krijanovski O, Gatza E, Liu C, Malter C, Mascagni P, Dinarello CA, Ferrara JLM (2008) Histone deacetylase inhibition modulates indoleamine 2, 3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. J Clin Invest 118(7):2562–2573PubMedGoogle Scholar
  83. 83.
    Brem-Exner BG, Sattler C, Hutchinson JA, Koehl GE, Kronenberg K, Farkas S, Inoue S, Blank C, Knechtle SJ, Schlitt HJ, Fandrich F, Geissler EK (2008) Macrophages driven to a novel state of activation have anti-inflammatory properties in mice. J Immunol 180(1):335–349PubMedGoogle Scholar
  84. 84.
    Fandrich F, Lin XB, Chai GX, Schulze M, Ganten D, Bader M, Holle J, Huang DS, Parwaresch R, Zavazava N, Binas B (2002) Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning. Nat Med 8(2):171–178PubMedGoogle Scholar
  85. 85.
    Hutchinson JA, Riquelme P, Brem-Exner BG, Schulze M, Matthai M, Renders L, Kunzendorf U, Geissler EK, Fandrich F (2008) Transplant acceptance-inducing cells as an immune-conditioning therapy in renal transplantation. Transpl Int 21(8):728–741PubMedGoogle Scholar
  86. 86.
    Hutchinson JA, Brem-Exner BG, Riquelme P, Roelen D, Schulze M, Ivens K, Grabensee B, Witzke O, Philipp T, Renders L, Humpe A, Sotnikova A, Matthai M, Heumann A, Govert F, Schulte T, Kabelitz D, Claas FHJ, Geissler EK, Kunzendorf U, Fandrich F (2008) A cell-based approach to the minimization of immunosuppression in renal transplantation. Transpl Int 21(8):742–754PubMedGoogle Scholar
  87. 87.
    Hutchinson JA, Roelen D, Riquelme P, Brem-Exner BG, Witzke O, Philipp T, Matthai M, Govert F, Claas FHJ, Westphal E, Kunzendorf U, Geissler EK, Fandrich F (2008) Preoperative treatment of a presensitized kidney transplant recipient with donor-derived transplant acceptance-inducing cells. Transpl Int 21(8):808–813PubMedGoogle Scholar
  88. 88.
    Riquelme P, Govert F, Geissler EK, Fandrich F, Hutchinson JA (2009) Human transplant acceptance-inducing cells suppress mitogen-stimulated T cell proliferation. Transpl Immunol 21(3):162–165PubMedGoogle Scholar
  89. 89.
    Hutchinson JA, Riquelme P, Geissler EK, Fandrich F (2009) Macrophages driven to a novel state of activation have tolerogenic properties in kidney transplant recipients. Am J Transplant 9:657–657Google Scholar
  90. 90.
    Hutchinson JA, Govert F, Riquelme P, Brasen JH, Brem-Exner BG, Matthai M, Schulze M, Renders L, Kunzendorf U, Geissler EK, Fandrich F (2009) Administration of donor-derived transplant acceptance-inducing cells to the recipients of renal transplants from deceased donors is technically feasible. Clin Transplant 23(1):140–145PubMedGoogle Scholar
  91. 91.
    Castellaneta A, Thomson AW, Nayyar N, de Vera M, Mazariegos GV (2010) Monitoring the operationally tolerant liver allograft recipient. Curr Opin Organ Transplant 15(1):28–34PubMedGoogle Scholar
  92. 92.
    Martinez-Llordella M, Lozano JJ, Puig-Pey I, Orlando G, Tisone G, Lerut J, Benitez C, Pons JA, Parrilla P, Ramirez P, Bruguera M, Rimola A, Sanchez-Fueyo A (2008) Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients. J Clin Invest 118(8):2845–2857PubMedGoogle Scholar
  93. 93.
    Batista FD, Iber D, Neuberger MS (2001) B cells acquire antigen from target cells after synapse formation. Nature 411(6836):489–494PubMedGoogle Scholar
  94. 94.
    Lund FE, Randall TD (2010) Effector and regulatory B cells: modulators of CD4(+) T cell immunity. Nat Rev Immunol 10(4):236–247PubMedGoogle Scholar
  95. 95.
    Pistoia V (1997) Production of cytokines by human B cells in health and disease. Immunol Today 18(7):343–350PubMedGoogle Scholar
  96. 96.
    Harris DP, Haynes L, Sayles PC, Duso DK, Eaton SM, Lepak NM, Johnson LL, Swain SL, Lund FE (2000) Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol 1(6):475–482PubMedGoogle Scholar
  97. 97.
    Thaunat O, Field AC, Dai JP, Louedec L, Patey N, Bloch MF, Mandet C, Belair MF, Bruneval P, Meilhac O, Bellon B, Joly E, Michel JB, Nicoletti A (2005) Lymphoid neogenesis in chronic rejection: evidence for a local humoral alloimmune response. Proc Natl Acad Sci USA 102(41):14723–14728PubMedGoogle Scholar
  98. 98.
    Aloisi F, Pujol-Borrell R (2006) Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 6(3):205–217PubMedGoogle Scholar
  99. 99.
    Matsushita T, Horikawa M, Iwata Y, Tedder TF (2010) Regulatory B cells (B10 Cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis. J Immunol 185(4):2240–2252PubMedGoogle Scholar
  100. 100.
    Clatworthy MR, Watson CJE, Plotnek G, Bardsley V, Chaudhry AN, Bradley JA, Smith KGC (2009) B-cell-depleting induction therapy and acute cellular rejection. N Engl J Med 360(25):2683–2685PubMedGoogle Scholar
  101. 101.
    Sawitzki B, Bushell A, Steger U, Jones N, Risch K, Siepert A, Lehmann M, Schmitt-Knosalla I, Vogt K, Gebuhr I, Wood K, Volk HD (2007) Identification of gene markers for the prediction of allograft rejection or permanent acceptance. Am J Transplant 7(5):1091–1102PubMedGoogle Scholar
  102. 102.
    Karam VH, Gasquet I, Delvart V, Hiesse C, Dorent R, Danet C, Samuel D, Charpentier B, Gandjbakhch I, Bismuth H, Castaing D (2003) Quality of life in adult survivors beyond 10 years after liver, kidney, and heart transplantation. Transplantation 76(12):1699–1704PubMedGoogle Scholar
  103. 103.
    Tisone G, Orlando G, Angelico M (2007) Operational tolerance in clinical liver transplantation: emerging developments. Transpl Immunol 17(2):108–113PubMedGoogle Scholar
  104. 104.
    Strober S, Lowsky RJ, Shizuru JA, Scandling JD, Millan MT (2004) Approaches to transplantation tolerance in humans. Transplantation 77(6):932–936PubMedGoogle Scholar
  105. 105.
    Takatsuki M, Uemoto S, Inomata Y, Egawa H, Kiuchi T, Fujita S, Hayashi M, Kanematsu T, Tanaka K (2001) Weaning of immunosuppression in living donor liver transplant recipients. Transplantation 72(3):449–454PubMedGoogle Scholar
  106. 106.
    Koshiba T, Li Y, Takemura M, Wu YL, Sakaguchi S, Minato N, Wood KJ, Haga H, Ueda M, Uemoto S (2007) Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol 17(2):94–97PubMedGoogle Scholar
  107. 107.
    Li Y, Koshiba T, Yoshizawa A, Ito A, Egawa H, Sakaguchi S, Minato N, Wood KJ, Tanaka K (2004) Analysis of peripheral blood mononuclear cells in operational tolerance after living-donor liver transplantation (LDLT). Am J Transplant 4:445Google Scholar
  108. 108.
    Yoshizawa A, Ito A, Li Y, Koshiba T, Sakaguchi S, Wood KJ, Tanaka K (2005) The roles of CD25+CD4+ regulatory T cells in operational tolerance after living donor liver transplantation. Transplant Proc 37(1):37–39PubMedGoogle Scholar
  109. 109.
    Pons JA, Ramirez P, Revilla-Nuin B, Pascual D, Baroja-Mazo A, Robles R, Sanchez-Bueno F, Martinez L, Parrilla P (2009) Immunosuppression withdrawal improves long-term metabolic parameters, cardiovascular risk factors and renal function in liver transplant patients. Clin Transplant 23(3):329–336PubMedGoogle Scholar
  110. 110.
    Yoshitomi M, Koshiba T, Haga H, Li Y, Zhao X, Cheng D, Miyagawa A, Sakashita H, Tsuruyama T, Ohe H, Ueda M, Okamoto S, Egawa H, Wood K, Sakaguchi S, Manabe T, Tanaka K, Uemoto S (2009) Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation 87(4):606–614PubMedGoogle Scholar
  111. 111.
    Kawamoto K, Pahuja A, Hering BJ, Bansal-Pakala P (2010) Transforming growth factor beta 1 (TGF-beta 1) and rapamycin synergize to effectively suppress human T cell responses via upregulation of FoxP3(+) Tregs. Transpl Immunol 23(1–2):28–33PubMedGoogle Scholar
  112. 112.
    Morelon E, Lefrancois N, Besson C, Prevautel J, Brunet M, Touraine JL, Badet L, Touraine-Moulin F, Thaunat O, Malcus C (2010) Preferential increase in memory and regulatory subsets during T-lymphocyte immune reconstitution after Thymoglobulin induction therapy with maintenance sirolimus vs cyclosporine. Transpl Immunol 23(1–2):53–58PubMedGoogle Scholar
  113. 113.
    Ma AL, Qi SJ, Wang ZY, Massicotte E, Dupuis M, Daloze P, Chen HF (2009) Combined therapy of CD4(+)CD25(+) regulatory T cells with low-dose sirolimus, but not calcineurin inhibitors, preserves suppressive function of regulatory T cells and prolongs allograft survival in mice. Inter Immunopharmacol 9(5):553–563Google Scholar
  114. 114.
    De Serres SA, Sayegh MH, Najafian N (2009) Immunosuppressive drugs and Tregs: a critical evaluation! Clinical J Am Soc Nephrol 4(10):1661–1669Google Scholar
  115. 115.
    Segundo DS, Fabrega E, Lopez-Hoyos M, Pons F (2007) Reduced numbers of blood natural regulatory T cells in stable liver transplant recipients with high levels of calcineurin inhibitors. Transplant Proc 39(7):2290–2292Google Scholar
  116. 116.
    Alberu J, Urrea EM (2005) Immunosuppression for kidney transplant recipients: current strategies. Rev Invest Clin 57(2):213–224PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  1. 1.Department of Applied Cellular MedicineUniversity Schleswig-Holstein, Campus KielKielGermany

Personalised recommendations