Langenbeck's Archives of Surgery

, Volume 392, Issue 5, pp 511–523 | Cite as

Current concepts and perspectives of immunosuppression in organ transplantation

  • Marcus N. Scherer
  • Bernhard Banas
  • Kiriaki Mantouvalou
  • Andreas Schnitzbauer
  • Aiman Obed
  • Bernhard K. Krämer
  • Hans J. Schlitt
Current Concepts in Clinical Surgery

Abstract

Background

While early surgical success made organ transplantation possible in the 1950s and 1960s, the breakthrough in clinical organ transplantation was achieved through the discovery and invention of modern immunosuppressive agents in the early/mid-1980s. Especially during the 1990s, a large array of immunosuppressants has expanded the armamentarium used to prevent and treat allograft rejection, resulting in an excellent short-term and an acceptable long-term outcome. However, these drugs have potent but still non-specific immunosuppressive properties and frequently show severe acute and chronic side effects, sometimes questioning the overall success.

Concepts/Trends

As the “Holy-Grail” of the transplant community, the induction of “true donor-specific tolerance” has not been achieved yet; current immunosuppressive strategies, in particular in Europe, include “individually tailored immunosuppressive” protocols, mostly based on specific immunologic and non-immunologic risk factors. These protocols allow for optimal immunosuppressive protocols for each patient group according to their needs by choosing the most suitable, well-tolerated combination of agents and the most effective doses to avoid acute rejection episodes (incidence and severity) and minimise drug-related toxicity to reduce long-term drug-related morbidity and mortality. Nevertheless, transplant recipient are still being forced to take a life-long course of chemical immunosuppressive agents to keep their graft, knowing about the possible life-threatening side effects.

Summary

We review current trends of immunosuppressive protocols in liver and kidney transplantation, focusing on calcineurin-inhibitor-sparing protocols, mammalian-target-of-rapamycin (mTOR) inhibitor based-protocols and corticosteroid-avoidance protocols, being aware of the fact, that most of these strategies could be applicable for other transplanted organs, too. Finally, we describe future trends and new developments that are rising on the horizon.

Keywords

Individually tailored immunosuppression Drug-related side effects Calcineurin-inhibitor-sparing Steroid-avoidance mTOR inhibitor Impaired renal function De-novo/recurrence of cancer True/prope tolerance 

References

  1. 1.
    Calmus Y, Scheele JR, Gonzalez-Pinto I, Jaurietta EJ, Klar E, Pageaux GP, Scudamore CH, Cuervas-Mons V, Metselaar HJ, Prestele H, Girault D (2002) Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with azathioprine-containing triple therapy in liver transplant recipients. Liver Transplant 8:123–131Google Scholar
  2. 2.
    Neuhaus P, Clavien PA, Kittur D, Salizzoni M, Rimola A, Abeywickrama K, Ortmann E, Chodoff l, Hall M, Korn A, Nashan B (2002) CHIC 304 International liver study group improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial. Liver Transplant 8:132–142Google Scholar
  3. 3.
    Knechtle SJ, Pirsch JD, H Fechner J Jr, Becker BN, Friedl A, Colvin RB, Lebeck LK, Chin LT, Becker YT, Odorico JS, D’Alessandro AM, Kalayoglu M, Hamawy MM, Hu H, Bloom DD, Sollinger HW (2003) Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant Jun 3(6):722–730Google Scholar
  4. 4.
    Knechtle SJ, Fernandez LA, Pirsch JD, Becker BN, Chin LT, Becker YT, Odorico JS, D’alessandro AM, Sollinger HW (2004) Campath-1H in renal transplantation: the University of Wisconsin experience. Surgery 136(4):754–760PubMedGoogle Scholar
  5. 5.
    Bloom DD, Hu H, Fechner JH, Knechtle SJ (2006) Lymphocyte alloresponses of Campath-1H-treated kidney transplant patients. Transplantation 81(1):81–87PubMedGoogle Scholar
  6. 6.
    Magliocca JF, Knechtle SJ (2006) The evolving role of alemtuzumab (Campath-1H) for immunosuppressive therapy in organ transplantation. Transpl Int 19(9):705–714PubMedGoogle Scholar
  7. 7.
    Knechtle SJ (2005) How does alemtuzumab affect long-term graft and patient outcomes after deceased-donor kidney transplantation? Nat Clin Pract Nephrol Dez 1(2):74–75Google Scholar
  8. 8.
    Barth RN, Janus CA, Lillesand CA, Radke NA, Pirsch JD, Becker BN, Fernandez LA, Thomas Chin L, Becker YT, Odorico JS, D’Alessandro AM, Sollinger HW, Knechtle SJ (2006) Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation. Transpl Int 19(11):885–895PubMedGoogle Scholar
  9. 9.
    Morris PJ, Russell NK (2006) Alemtuzumab (Campath-1H): a systematic review in organ transplantation. Transplantation 81(10):1361–1367PubMedGoogle Scholar
  10. 10.
    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
  11. 11.
    Calne R, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, Firth J, Bradley J, Smith KG, Waldmann H (1999) Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation 68(10):1613–1616PubMedGoogle Scholar
  12. 12.
    Marcos A, Eghtesad B, Fung JJ, Fontes P, Patel K, Devera M, Marsh W, Gayowski T, Demetris AJ, Gray EA, Flynn B, Zeevi A, Murase N, Starzl TE (2004) Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus. Transplantation 78:966–971PubMedGoogle Scholar
  13. 13.
    Opelz G, Döhler B (2003) Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 4:222–230Google Scholar
  14. 14.
    Bustami RT, Ojo AO, Wolfe RA, Merion RM, Bennett WM, McDiarmid SV, Leichtman AB, Held PJ, Port FK (2004) Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 4:87–93PubMedGoogle Scholar
  15. 15.
    Haddad EM, Mc Alister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL (2006) Cyclosporin versus tacrolismus for liver transplanted patients. Cochrane Database of Syst Rev 4:CD005161Google Scholar
  16. 16.
    Kaufman DB, Shapiro R, Lucey MR, Cherikh WS, Bustamie RT, Dyke BD (2004) Immunosuppression: practice and trends. Am J Transplant 4(Suppl 9):38–53PubMedGoogle Scholar
  17. 17.
    Ponticelli C (2005) Clinical experience with everolimus (Certican): a summary. Transplantation 79:93–94Google Scholar
  18. 18.
    Neff GW, Moltalbano M, Tzakis AG (2003) Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 35:209–216Google Scholar
  19. 19.
    Vivarelli M, Vetrone G, Zanello M, Barba GL, Cucchetti A, Lauro A, Grazi GL, Pinna AD (2006) Sirolimus as the main immunosuppressant in the early postoperative period following liver transplantation: a report of six cases and review of the literature. Transpl Int 19:1022–1225PubMedGoogle Scholar
  20. 20.
    McAlister VC, Peltekia KM, Malatjalian DA, Colohan S, MacDonald S, Bitter-Suermann H, MacDonald AS (2001) Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transplant 7(8):701–708Google Scholar
  21. 21.
    Watson CJ, Friend PJ, Jamieson NV, Frick TW, Alexander G, Gimson AE, Calne R (1999) Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67(4):505–509PubMedGoogle Scholar
  22. 22.
    Chang GJ, Mahanty HD, Quan D, Freise CE, Ascher NL, Roberts JP, Stock PG, Hirose R (2000) Experience with the use of sirolimus in liver transplantation-use in patients for whom calcineurin inhibitors are contraindicated. Liver Transplant 6(6):734–740Google Scholar
  23. 23.
    Cabezuelo JB, Ramirez P, Rios A, Acosta F, Torres D, Sansano T, Pons JA, Bru M, Montova M, Bueno FS, Robles R, Parrilla P (2006) Risk factors of acute renal failure after liver transplantation. Kidney Int 69:1073–1780PubMedGoogle Scholar
  24. 24.
    Lima EQ, Zanetta DM, Castro I, Massarollo PC, Mies S, Machado MM, Yu L (2003) Risk factors for development of acute renal failure after liver transplantation. Ren Fail 25:553–560PubMedGoogle Scholar
  25. 25.
    Larson TS, Dean PG, Stegall MD, Griffin MD, Textor SC, Schwab TR, Gloor JM, Cosio FG, Lund WJ, Kremers WK, Nyberg SL, Ishitani MB, Prieto M, Velosa JA (2006) Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 6:514–522PubMedGoogle Scholar
  26. 26.
    Hamdy AF, El-Agroudy AE, Bakr MA, Mostafa A, El-Baz M, El-Shahawy el-M, Ghoneim MA (2005) Comparison of sirolimus with low-dose tacrolimus versus sirolimus-based calcineurin inhibitor-free regimen in live donor renal transplantation. Am J Transplant 5:2531–2538PubMedGoogle Scholar
  27. 27.
    Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, Johnson R, Kuypers D, Stuart F, Khanna A, Navarro M, Nashan B (2001) Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation 71:1282–1287PubMedGoogle Scholar
  28. 28.
    Asberg A, Midtvedt K, Line PD, Narverud J, Holdaas H, Jenssen T, Reisaeter AV, Johsen LF, Fauchald P, Hartmann A (2006) Calcineurin inhibitor avoidance with daclizumab, mycophenolate mofetil, and prednisolone in DR-matched de novo kidney transplant recipients. Transplantation 82:62–68PubMedGoogle Scholar
  29. 29.
    Schlitt HJ, Barkmann A, Boker KH, Schmidt HH, Emmanouilidis N, Rosenau J, Bahr MJ, Tusch G, Manns MP, Nashan B, Klempnauer J (2001) Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet 357:587–591PubMedGoogle Scholar
  30. 30.
    Papatheodoridis GV, O’Beirne J, Mistry P, Davidson B, Rolles K, Burroughs AK (1999) Mycophenolate mofetil monotherapy in stable liver transplant patients with cyclosporine-induced renal impairment: a preliminary report. Transplantation 68(1):155–157PubMedGoogle Scholar
  31. 31.
    Herrero JI, Quiroga J, Sangro B, Girala M, Gomez-Manero N, Pardo F, Alvarez-Cienfuegos, Prieto J (1999) Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil. Liver Transpl Sur 5(5):414–420Google Scholar
  32. 32.
    Barkmann A, Nashan B, Schmidt HH, Boker KH, Emmanouilidis N, Rosenau J, Bahr MJ, Hoffmann MW, Manns MP, Klempnauer J, Schlitt HJ (2000) Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil. Transplantation 69(9):1886–1890PubMedGoogle Scholar
  33. 33.
    Yoshida EM, Marotta PJ, Greig PD, Kneteman NM, Marleau D, Cantarovich M, Peltekian KM, Lilly LB, Scudamore CH, Bain VG, Wall WJ, Roy A, Balshaw RF, Barkun JS (2005) Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial. Liver Transplant 11:1064–1072Google Scholar
  34. 34.
    Lin CC, Chuang FR, Lee CH, Wang CC, Chen YS, Liu YW, Jawan B, Chen CL (2005) The renal-sparing efficacy of basiliximab in adult living donor liver transplantation. Liver Transplant 11:1258–1264Google Scholar
  35. 35.
    Tchervenkov JI, Tzimas GN, Cantarovich M, Barkun JS, Metrakos P (2004) The impact of thymoglobulin on renal function and calcineurin inhibitor initiation in recipients of orthotopic liver transplant: a retrospective analysis of 298 consecutive patients. Transplant Proc 36:1747–1752PubMedGoogle Scholar
  36. 36.
    Kasiske BL, Snyder JJ, Gilbertson DT, Wang C (2004) Cancer after kidney transplantation in the United States. Am J Transplant 4(6):905–913PubMedGoogle Scholar
  37. 37.
    Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN (2002) Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol 147(5):950–956PubMedGoogle Scholar
  38. 38.
    Moloney FJ, Comber H, O’Lorcain P, O’Kelly P, Conlon PJ, Murphy GM (2006) A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 154(3):498–504PubMedGoogle Scholar
  39. 39.
    Carroll RP, Ramsay HM, Fryer AA, Hawley CM, Nicol DL, Harden PN (2003) Incidence and prediction of nonmelanoma skin cancer post-renal transplantation: a prospective study in Queensland, Australia. Am J Kidney Dis 41(3):676–683PubMedGoogle Scholar
  40. 40.
    Adami J, Gabel H, Lindelof B, Ekstrom K, Rydh B, Glimelius B, Ekbom A, Adami HO, Granath F (2003) Cancer risk following organ transplantation: a nationwide cohort study in Sweden. Br J Cancer 89(7):1221–1227PubMedGoogle Scholar
  41. 41.
    Marcil I, Stern RS (2001) Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet 358:1042–1045PubMedGoogle Scholar
  42. 42.
    Herman M, Weinstein T, Korzets A, Chagnac A, Zevin D, Malachi T, Gafter U (2001) Effect of cyclosporin A on DNA repair and cancer incidence in kidney transplant recipients. J Lab Clin Med 137:14–20PubMedGoogle Scholar
  43. 43.
    Freise CE, Ferrell L, Liu T, Ascher NL, Roberts JP (1999) Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma. Transplantation 67:510–513PubMedGoogle Scholar
  44. 44.
    Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M (1999) Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397(6719):530–534PubMedGoogle Scholar
  45. 45.
    Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, Soulillou JP (1998) Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 351(9103):623–628PubMedGoogle Scholar
  46. 46.
    Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK (2002) Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128–135PubMedGoogle Scholar
  47. 47.
    Luan FL, Ding R, Sharma VK, Chon WJ, Lagman M, Suthanthiran M (2003) Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 63:917–926PubMedGoogle Scholar
  48. 48.
    Koehl GE, Andrassy J, Guba M, Richter S, Kroemer A, Scherer MN, Steinbauer M, Graeb C, Schlitt HJ, Jauch KW, Geissler EK (2004) Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 77(9):1319–1326PubMedGoogle Scholar
  49. 49.
    Bruns CJ, Koehl GE, Guba M, Yezhelyev M, Steinbauer M, Seeliger H, Schwend A, Hoehn A, Jauch KW, Geissler EK (2004) Rapamycin-induced endothelial cell death and tumor vessel thrombosis potentiate cytotoxic therapy against pancreatic cancer. Clin Cancer Res 10(6):2109–2119PubMedGoogle Scholar
  50. 50.
    Koehl GE, Gaumann A, Zuelke C, Hoehn A, Hofstaedter F, Schlitt HJ, Geissler EK (2006) Development of de novo cancer in p53 knock-out mice is dependent on the type of long-term immunosuppression used.Transplantation 82(6):781–786Google Scholar
  51. 51.
    Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K, Mason AL, Jewll LD, Shapiro AM, Bain VG, Bigam DL (2004) Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transplant 10:1301–1311Google Scholar
  52. 52.
    Mazzaferro V, Regalia E, Montalto F, Pulvirenti A, Brunetto F, Lerut J, Gennari L (1996) Risk of HBV reinfection after liver transplantation in HBsAg-positive cirrhosis. Primary hepatocellular carcinoma is not a predictor for HBV recurrence. The European Cooperative Study Group on Liver Cancer and Transplantation. Liver 16:117–122PubMedGoogle Scholar
  53. 53.
    Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE Jr (2003) Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation 75:1396–1399PubMedGoogle Scholar
  54. 54.
    O’Grady JG (2006) Corticosteroid-free strategies in liver transplantation. Drugs 66:1853–1862PubMedGoogle Scholar
  55. 55.
    Tisone G, Angelico M, Orlando G, Palmieri GP, Strati F, Di Paolo D, Casciani CU (1999) Retrospective analysis of 30 patients who underwent liver transplantation without use of steroids. Transplant Proc 31:2908–2909PubMedGoogle Scholar
  56. 56.
    Trotter JF, Wachs M, Bak T, Trouillot T, Stolpman N, Everson GT, Kam I (2001) Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). Liver Transplant 7:343–351Google Scholar
  57. 57.
    Eason JD, Cohen AJ, Nair S, Alcantera T, Loss GE (2005) Tolerance: is it worth the risk? Transplantation 79:1157–1159PubMedGoogle Scholar
  58. 58.
    Eason JD, Loss GE, Blazek J, Nair S, Mason AL (2001) Steroid-free liver transplantation using rabbit antithymocyte globulin induction: results of a prospective randomized trial. Liver Transplant 7(8):693–697Google Scholar
  59. 59.
    Tisone G, Angelico M, Palmieri G, Pisani F, Anselmo A, Baiocchi L, Negrini S, Orlando G, Vennarecci G, Casciani CU (1999) A pilot study on the safety and effectiveness of immunosuppression without prednisone after liver transplantation. Transplantation 67(10):1308–1313PubMedGoogle Scholar
  60. 60.
    Pelletier SJ, Vanderwall K, Debroy MA, Englesbe MJ, Sung RS, Magee JC, Fontana RJ, Punch JD (2005) Preliminary analysis of early outcomes of a prospective, randomized trial of complete steroid avoidance in liver transplantation. Transplant Proc 37(2):1214–1216PubMedGoogle Scholar
  61. 61.
    Boillot O, Mayer DA, Boudjema K, Salizzoni M, Gridelli B, Filipponi F, Trunecka P, Krawczyk M, Clavien PA, Ducerf C, Margarit C, Margreiter R, Pallardo JM, Hoeckerstedt K, Pageaux GP (2005) Corticosteroid-free immunosuppression with tacrolimus following induction with daclizumab: a large randomized clinical study. Liver Transplant 11(1):61–67Google Scholar
  62. 62.
    Llado L, Xiol X, Figueras J, Ramos E, Memba R, Serrano T, Torras J, Garcia-Gil A, Gonzalez-Pinto I, Castellote J, Baliellas C, Fabregat J, Rafecas A, Thosin Study Group (2006) Immunosuppression without steroids in liver transplantation is safe and reduces infection and metabolic complications: results from a prospective multicenter randomized study. J Hepatol 44(4):710–716PubMedGoogle Scholar
  63. 63.
    Nair S, Loss GE, Cohen AJ, Eason JD (2006) Induction with rabbit antithymocyte globulin versus induction with corticosteroids in liver transplantation: impact on recurrent hepatitis C virus infection. Transplantation 81:620–622PubMedGoogle Scholar
  64. 64.
    Filipponi F, Callea F, Salizzoni M, Grazi GL, Fassati LR, Rossi M, Risaliti A, Burra P, Agnes S, De Carlis L, Valente U, Ferrara R, Pisati R (2004) Double-blind comparison of hepatitis C histological recurrence Rate in HCV+ liver transplant recipients given basiliximab + steroids or basiliximab + placebo, in addition to cyclosporine and azathioprine. Transplantation 78(10):1488–1495PubMedGoogle Scholar
  65. 65.
    Berenguer M, Aguilera V, Prieto M, San Juan F, Rayon JM, Benlloch S, Berenguer J (2006) Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression. J Hepatol 44:717–722PubMedGoogle Scholar
  66. 66.
    Brillanti S, Vivarelli M, De Ruvo N, Aden AA, Camaggi V, D’Errico A, Furlini G, Bellusci R, Roda E, Cavallari A (2002) Slowly tapering off steroids protects the graft against hepatitis C recurrence after liver transplantation. Liver Transplant 8(10):884–888Google Scholar
  67. 67.
    Marik PE, Gayowski T, Starzl TE, Hepatic Cortisol Research and Adrenal Pathophysiology Study Group (2005) The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med 33:1254–1259PubMedGoogle Scholar
  68. 68.
    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 4:378–383PubMedGoogle Scholar
  69. 69.
    Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D (2000) Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 342:605–612PubMedGoogle Scholar
  70. 70.
    Kahan BD (2003) Individuality: the barrier to optimal immunosuppression. Nat Rev Immunol 3:831–838PubMedGoogle Scholar
  71. 71.
    Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP (1997) Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 350:1193–1198PubMedGoogle Scholar
  72. 72.
    Nashan B, Light S, Hardie IR, Lin A, Johnson JR (1999) Reduction of acute renal allograft rejection by daclizumab. Daclizumab Double Therapy Study Group. Transplantation 67:110–115PubMedGoogle Scholar
  73. 73.
    Webster AC, Playford EG, Higgins G, Chapman JR, Craig JC (2004) Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation 77:166–176PubMedGoogle Scholar
  74. 74.
    Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, Smith KG, Thiru S, Jamieson NV, Hale G, Waldmann H, Calne R (2005) Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation-efficacy and safety at five years. Am J Transplant 5:1347–1353PubMedGoogle Scholar
  75. 75.
    Ducloux D, Kazory A, Challier B, Coutet J, Bresson-Vautrin C, Motte G, Thalamy B, Rebibou JM, Chalopin JM (2004) Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study. Transplantation 77:1029–1033PubMedGoogle Scholar
  76. 76.
    Kasiske BL, Chakkera HA, Louis TA, Ma JZ (2000) A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 11:1910–1917PubMedGoogle Scholar
  77. 77.
    Pascual J, Quereda C, Zamora J, Hernandez D, Spanish Group for Evidence-Based Medicine in Renal Transplantation (2004) Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation 78:1548–1556PubMedGoogle Scholar
  78. 78.
    Opelz G, Dohler B, Laux G, Collaborative Transplant Study (2005) Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients. Am J Transplant 5:720–728PubMedGoogle Scholar
  79. 79.
    Wlodarczyk Z, Walaszewski J, Perner F, Vitko S, Ostrowski M, Bachleda P, Kokot F, Klinger M, Szenohradszky P, Studenik P, Navratil P, Asztalos L, Rutkowski B, Nagy KK, Hickey D (2002) Freedom from rejection and stable kidney function are excellent criteria for steroid withdrawal in tacrolimus-treated kidney transplant recipients. Ann Transplant 7:28–31PubMedGoogle Scholar
  80. 80.
    Wlodarczyk Z, Walaszewski J, Perner F, Vitko S, Ostrowski M, Bachleda P, Kokot F, Klinger M, Szenohradszky P, Studenik P, Navratil P, Asztalos L, Rutkowski B, Kalmar KN, Hickey D (2005) Steroid withdrawal at 3 months after kidney transplantation: a comparison of two tacrolimus-based regimens. Transpl Int 18:157–162PubMedGoogle Scholar
  81. 81.
    Vanrenterghem Y, van Hooff JP, Squifflet JP, Salmela K, Rigotti P, Jindal RM, Pascual J, Ekberg H, Sicilia LS, Boletis JN, Grinyo JM, Rodriguez MA, European Tacrolimus/MMF Renal Transplantation Study Group (2005) Minimization of immunosuppressive therapy after renal transplantation: results of a randomized controlled trial. Am J Transplant 5:87–95PubMedGoogle Scholar
  82. 82.
    Smak Gregoor PJ, de Sevaux RG, Ligtenberg G, Hoitsma AJ, Hene RJ, Weimar W, Hilbrands LB, van Gelder T (2002) Withdrawal of cyclosporine or prednisone six months after kidney transplantation in patients on triple drug therapy: a randomized, prospective, multicenter study. J Am Soc Nephrol 13:1365–1373PubMedGoogle Scholar
  83. 83.
    Cole E, Landsberg D, Russell D, Zaltzman J, Kiberd B, Caravaggio C, Vasquez AR, Halloran P (2001) A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation 72:845–850PubMedGoogle Scholar
  84. 84.
    Rostaing L, Cantarovich D, Mourad G, Budde K, Rigotti P, Mariat C, Margreiter R, Capdevilla L, Lang P, Vialtel P, Ortuno-Mirete J, Charpentier B, Legendre C, Sanchez-Plumed J, Oppenheimer F, Kessler M, CARMEN Study Group (2005) Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 79:807–814PubMedGoogle Scholar
  85. 85.
    Vitko S, Klinger M, Salmela K, Wlodarczyk Z, Tyden G, Senatorski G, Ostrowski M, Fauchald P, Kokot F, Stefoni S, Perner F, Claesson K, Castagneto M, Heemann U, Carmellini M, Squifflet JP, Weber M, Segoloni G, Backman L, Sperschneider H, Kramer BK (2005) Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study. Transplantation 80:1734–1741PubMedGoogle Scholar
  86. 86.
    Kreis H, Cisterne JM, Land W, Wrammer L, Squifflet JP, Abramowicz D, Campistol JM, Morales JM, Grinyo JM, Mourad G, Berthoux FC, Brattstrom C, Lebranchu Y, Vialtel P (2000) Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 69:1252–1260PubMedGoogle Scholar
  87. 87.
    Flechner SM, Goldfarb D, Modlin C, Feng J, Krishnamurthi V, Mastroianni B, Savas K, Cook DJ, Novick AC (2002) Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 74:1070–1076PubMedGoogle Scholar
  88. 88.
    Larson TS, Dean PG, Stegall MD, Textor SC, Schwab TR, Gloor JM, Cosio FG, Lund WJ, Kremers WK, Nyberg SL, Ishitani MB, Prieto M, Velosa JA (2006) Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 6:514–522PubMedGoogle Scholar
  89. 89.
    Johnson RW, Kreis H, Oberbauer R, Brattstrom C, Claesson K, Eris J (2001) Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 72:777–786PubMedGoogle Scholar
  90. 90.
    Vitko S, Margreiter R, Weimar W, Dantal J, Viljoen HG, Li Y, Jappe A, Cretin N, RAD B201 Study Group (2004) Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 78:1532–1540PubMedGoogle Scholar
  91. 91.
    Nashan B, Curtis J, Ponticelli C, Mourad G, Jaffe J, Haas T, 156 Study Group (2004) Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study. Transplantation 78:1332–1340PubMedGoogle Scholar
  92. 92.
    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 361:1502–1510PubMedGoogle Scholar
  93. 93.
    Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O’Shea JJ, Borie DC (2003) Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302(5646):875–878PubMedGoogle Scholar
  94. 94.
    Borie DC, Larson MJ, Flores MG, Campbell A, Rousvoal G, Zhang S, Higgins JP, Ball DJ, Kudlacz EM, Brissette WH, Elliott EA, Reitz BA, Changelian PS (2005) Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. Transplantation 80(12):1756–1764PubMedGoogle Scholar
  95. 95.
    Hirose R, Vincenti F (2006) Immunosuppression: today, tomorrow and withdrawal. Semin Liver Dis 26:201–210PubMedGoogle Scholar
  96. 96.
    Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G, Lang P, Grinyo J, Halloran PF, Solez K, Hagerty D, Levy E, Zhou W, Natarajan K, Charpentier B, Belatacept Study Group (2005) Costimulation blockade with belatacept in renal transplantation. N Engl J Med 353:770–781PubMedGoogle Scholar
  97. 97.
    Adams AB, Shirasugi N, Jones TR, Durham MM, Strobert EA, Cowan S, Rees P, Hendrix R, Price K, Kenyon NS, Hagerty D, Townsend R, Hollenbaugh D, Pearson TC, Larsen CP (2005) Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival. J Immunol 174(1):542–550PubMedGoogle Scholar
  98. 98.
    Benseler V, McCaughan G, Schlitt HJ, Bishop GA, Bowen DG, Bertolino P (2007) Experimental models and clinical relevance of spontaneous liver transplant acceptance: facts and mechanisms. Semin Liver Dis (in press)Google Scholar
  99. 99.
    Ashton-Chess J, Brouard S, Soulillou JP (2006) Is clinical tolerance realistic in the next decade? Transpl Int 19(7):539–548PubMedGoogle Scholar
  100. 100.
    Roussey-Kesler G, Giral M, Moreau A, Subra JF, Legendre C, Noeal, et al (2006) Clinical operational tolerance after kidney transplantation. Am J Transplantation 6(4):736–746Google Scholar
  101. 101.
    Knechtle SJ, Burlingham WJ (2004) Metastable tolerance in nonhuman primates and humans. Transplantation 77(6):936–939PubMedGoogle Scholar
  102. 102.
    Torrealba JR, Katayama M, Fechner JH Jr, Jankowska-Gan E, Kusaka S, Xu Q, Schultz M, Oberley TD, Hu H, Hamawy MM, Jonker M, Wubben J, Doxiadis G, Bontrop R, Burlingham J, Knechtle SJ (2004) Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-beta 1+CD4+ T regulatory cell infiltrates. J Immunol 172(9):5753–5764PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Marcus N. Scherer
    • 1
  • Bernhard Banas
    • 2
  • Kiriaki Mantouvalou
    • 1
  • Andreas Schnitzbauer
    • 1
  • Aiman Obed
    • 1
  • Bernhard K. Krämer
    • 2
  • Hans J. Schlitt
    • 1
  1. 1.Klinik und Poliklinik für Chirurgie und TransplantationKlinikum der Universität RegensburgRegensburgGermany
  2. 2.Klinik und Poliklinik für Innere Medizin IIKlinikum der Universität RegensburgRegensburgGermany

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