Immunosuppression for lung transplantation

Proceedings of the American Thoracic Society

Volumn 6, Issue 1, 2009, Pages 47-53

  Bhorade, Sangeeta M ^a   Stern, Eric ^a  

^a UNIVERSITY OF CHICAGO MEDICAL CENTER   (United States)

Author keywords

Immunosuppression; Lung transplantation

Indexed keywords

ALEMTUZUMAB; ALLOPURINOL; ANTACID AGENT; ANTIMETABOLITE; AZATHIOPRINE; BASILIXIMAB; CALCINEURIN INHIBITOR; COLESTYRAMINE; CORTICOSTEROID; CYCLOSPORIN A; DACLIZUMAB; DIPHENHYDRAMINE; EVEROLIMUS; IRON SALT; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; METHOXSALEN; METHYLPREDNISOLONE; MYCOPHENOLIC ACID; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; OKT 3; PARACETAMOL; PLACEBO; PREDNISOLONE; PREDNISONE; RAPAMYCIN; TACROLIMUS; THYMOCYTE ANTIBODY; TIOGUANINE;

ACNE; ACUTE GRAFT REJECTION; ADULT RESPIRATORY DISTRESS SYNDROME; ALLOIMMUNITY; ANAPHYLAXIS; APOPTOSIS; ARTHRALGIA; ASEPTIC MENINGITIS; BONE MARROW SUPPRESSION; BRONCHIOLITIS OBLITERANS; CELL SURVIVAL; CHILL; CHRONIC GRAFT REJECTION; CLINICAL TRIAL; CUSHINGOID SYNDROME; CYTOKINE RELEASE SYNDROME; DIABETES MELLITUS; DIARRHEA; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSAGE FORM COMPARISON; DRUG EFFICACY; DRUG HALF LIFE; DRUG HYPERSENSITIVITY; DRUG INHIBITION; DRUG MECHANISM; DRUG MEGADOSE; DRUG POTENCY; DRUG SAFETY; DRUG SUBSTITUTION; DRUG WITHDRAWAL; DYSLIPIDEMIA; ELECTROLYTE DISTURBANCE; ENTERIC COATED TABLET; ERYTHEMA; FEVER; FOOD; FOOD DRUG INTERACTION; GASTROINTESTINAL SYMPTOM; GINGIVA HYPERPLASIA; GLOMERULONEPHRITIS; GOUT; GRAFT RECIPIENT; GRAFT SURVIVAL; GROWTH RETARDATION; HEADACHE; HEMATURIA; HEMODIALYSIS; HEMOLYTIC UREMIC SYNDROME; HIRSUTISM; HUMAN; HYPERTENSION; HYPERURICEMIA; IMMUNE COMPLEX MEDIATED GLOMERULONEPHRITIS; IMMUNOREACTIVITY; IMMUNOSUPPRESSIVE TREATMENT; INTERSTITIAL PNEUMONIA; KIDNEY DYSFUNCTION; KIDNEY FAILURE; LEUKOPENIA; LIVER TOXICITY; LUNG ALVEOLITIS; LUNG EDEMA; LUNG HEMORRHAGE; LUNG TRANSPLANTATION; LYMPH NODE IRRADIATION; LYMPHOCYTIC ALVEOLITIS; LYMPHOPROLIFERATIVE DISEASE; MYALGIA; NEPHROTOXICITY; ORGANIZING PNEUMONIA; OSTEOPOROSIS; PANCYTOPENIA; PAROXYSMAL NOCTURNAL HEMATURIA; PEPTIC ULCER; PULMONARY VASCULITIS; PUVA; RADIATION DOSE; REGULATORY T LYMPHOCYTE; REVIEW; SEIZURE; SERUM SICKNESS; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; T LYMPHOCYTE ACTIVATION; THROMBOCYTOPENIA; THROMBOTIC THROMBOCYTOPENIC PURPURA; TREATMENT OUTCOME; TREMOR; UNSPECIFIED SIDE EFFECT; VIRUS INFECTION; WOUND HEALING IMPAIRMENT;

GRAFT REJECTION; GRAFT SURVIVAL; HUMANS; IMMUNOSUPPRESSION; IMMUNOSUPPRESSIVE AGENTS; LUNG TRANSPLANTATION; SALVAGE THERAPY;

EID: 58549103517     PISSN: 15463222     EISSN: None     Source Type: Journal    
DOI: 10.1513/pats.200808-096GO     Document Type: Review

References (90)

1. Dalton ML. The first lung transplant. Am Surg 2004;70:364-365.
2. Hardy JD. The first lung transplant in man (1963) and the first heart transplant in man (1964). Transplant Proc 1999;31:25-29.
3. McKane BW, Trulock EP, Patterson GA, Mohanakumar T. Lung transplantation and bronchiolitis obliterans: an evolution in understanding. Immunol Res 2001;24:177-190.
4. Date H. Current status and future of lung transplantation. Intern Med 2001;40:87-95.
5. Bracken CA, Gurkowski MA, Naples JJ. Lung transplantation: historical perspective, current concepts, and anesthetic considerations. J Cardiothorac Vasc Anesth 1997;11:220-241.
6. Valentine VG, Bonvillain RW, Gupta MR, Lombard GA, LaPlace SG, Dhillon GS, Wang G. Infections in lung allograft recipients: ganciclovir era. J Heart Lung Transplant 2008;27:528-535.
7. Kahan BD. The era of cyclosporine: twenty years forward, twenty years back. Transplant Proc 2004;36:5S-6S.
8. Kostakis A. Early experience with cyclosporine: a historic perspective. Transplant Proc 2004;36:22S-24S.
9. Parekh K, Trulock E, Patterson GA. Use of cyclosporine in lung transplantation. Transplant Proc 2004;36:318S-322S.
10. Lake KD. Immunosuppressive drugs and novel strategies to prevent acute and chronic allograft rejection. Semin Respir Crit Care Med 2001;22:559-580.
11. Demirkiran A, Hendrikx TK, Baan CC, van der Laan LJ. Impact of immunosuppressive drugs on CD4+CD25+FOXP3+ regulatory T cells: does in vitro evidence translate to the clinical setting? Transplantation 2008;85:783-789.
12. Korczak-Kowalska G, Wierzbicki P, Bocian K, Klosowska D, Niemczyk M, Wyzgal J, Korecka A, Durlik M, Chmura A, Paczek L, et al. The influence of immuosuppressive therapy on the development of CD4+CD25+ T cells after renal transplantation. Transplant Proc 2007;39:2721-2723.
13. Kapturczak MH, Meier-Kriesche HU, Kaplan B. Pharmacology of calcineurin antagonists. Transplant Proc 2004;36:25S-32S.
14. Jaksch P, Kocher A, Neuhauser P, Sarahrudi K, Seweryn J, Wisser W, Klepetko W. Monitoring c2 level predicts exposure in maintenance lung transplant patients receiving the microemulsion formulation of cyclosporine (neoral). J Heart Lung Transplant 2005;24:1076-1080.
15. Glanville AR, Morton JM, Aboyoun CL, Plit ML, Malouf MA. Cyclosporine c2 monitoring improves renal dysfunction after lung transplantation. J Heart Lung Transplant 2004;23:1170-1174.
16. Fellstrom B. Cyclosporine nephrotoxicity. Transplant Proc 2004;36:220S-223S.
17. Taylor JL, Palmer SM. Critical care perspective on immunotherapy in lung transplantation. J Intensive Care Med 2006;21:327-344.
18. Reichenspurner H. Overview of tacrolimus-based immunosuppression after heart or lung transplantation. J Heart Lung Transplant 2005;24:119-130.
19. Hausen B, Morris RE. Review of immunosuppression for lung transplantation. Novel drugs, new uses for conventional immunosuppressants, and alternative strategies. Clin Chest Med 1997;18:353-366.
20. Bush EL, Lin SS. Lung transplantation: advances in immunosuppression. Thorac Surg Clin 2006;16:421-433.
21. Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest 2003;111:1122-1124.
22. Taylor AL, Watson CJ, Bradley JA. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005;56:23-46.
23. Poppe D, Tiede I, Fritz G, Becker C, Bartsch B, Wirtz S, Strand D, Tanaka S, Galle PR, Bustelo XR, et al. Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-apc conjugation through inhibition of vav guanosine exchange activity on rac proteins. J Immunol 2006;176:640-651.
24. Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, Lehr HA, Wirtz S, Becker C, Atreya R, et al. CD28-dependent rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 2003;111:1133-1145.
25. Brooks RJ, Dorr RT, Durie BG. Interaction of allopurinol with 6-mercaptopurine and azathioprine. Biomed Pharmacother 1982;36:217-222.
26. Coffey JJ, White CA, Lesk AB, Rogers WI, Serpick AA. Effect of allopurinol on the pharmacokinetics of 6-mercaptopurine (nsc 755) in cancer patients. Cancer Res 1972;32:1283-1289.
27. Relling MV, Hancock ML, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH, Evans WE. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999;91:2001-2008.
28. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980;32:651-662.
29. Holme SA, Duley JA, Sanderson J, Routledge PA, Anstey AV. Erythrocyte thiopurine methyl transferase assessment prior to azathioprine use in the UK. QJM 2002;95:439-444.
30. Allison AC, Eugui EM. Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 2005;80:S181-S190.
31. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47:85-118.
32. Glanemann M, Klupp J, Langrehr JM, Schroer G, Platz KP, Stange B, Settmacher U, Bechstein WO, Neuhaus P. Higher immunosuppressive efficacy of mycophenolate mofetil in combination with fk 506 than in combination with cyclosporine a. Transplant Proc 2000;32:522-523.
33. Sollinger HW. Mycophenolates in transplantation. Clin Transplant 2004;18:485-492.
34. Kobashigawa JA, Renlund DG, Gerosa G, Almenar L, Eisen HJ, Keogh AM, Lehmkuhl HB, Livi U, Ross H, Segovia J, et al. Similar efficacy and safety of enteric-coated mycophenolate sodium (ec-mps, myfortic) compared with mycophenolate mofetil (MMF) in de novo heart transplant recipients: results of a 12-month, single-blind, randomized, parallel-group, multicenter study. J Heart Lung Transplant 2006;25:935-941.
35. Budde K, Curtis J, Knoll G, Chan L, Neumayer HH, Seifu Y, Hall M. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 2004;4:237-243.
36. Saunders RN, Metcalfe MS, Nicholson ML. Rapamycin in transplantation: a review of the evidence. Kidney Int 2001;59:3-16.
37. Kahan BD. Sirolimus: a ten-year perspective. Transplant Proc 2004;36:71-75.
38. Terada N, Lucas JJ, Szepesi A, Franklin RA, Domenico J, Gelfand EW. Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late g1 phase of the cycle. J Cell Physiol 1993;154:7-15.
39. Augustine JJ, Bodziak KA, Hricik DE. Use of sirolimus in solid organ transplantation. Drugs 2007;67:369-391.
40. King-Biggs MB, Dunitz JM, Park SJ, Kay Savik S, Hertz MI. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003;75:1437-1443.
41. Groetzner J, Kur F, Spelsberg F, Behr J, Frey L, Bittmann I, Vogeser M, Ueberfuhr P, Meiser B, Hatz R, et al. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004;23:632-638.
42. Meyer NJ, Bhorade SM. Evolving immunosuppressive regimens for lung transplant recipients. Semin Respir Crit Care Med 2006;27:470-479.
43. Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T, Wilkinson AH. Sirolimus-associated pulmonary toxicity. Transplantation 2004;77:1215-1220.
44. Chhajed PN, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M. Patterns of pulmonary complications associated with sirolimus. Respiration 2006;73:367-374.
45. McWilliams TJ, Levvey BJ, Russell PA, Milne DG, Snell GI. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. J Heart Lung Transplant 2003;22:210-213.
46. Doyle RL, Hertz MI, Dunitz JM, Loyd JE, Stecenko AA, Wong RL, Chappell KA, Brazelton T, Kovarik JM, Appeldingemanse S, et al. Rad in stable lung and heart/lung transplant recipients: safety, tolerability, pharmacokinetics, and impact of cystic fibrosis. J Heart Lung Transplant 2001;20:330-339.
47. Kovarik JM, Snell GI, Valentine V, Aris R, Chan CK, Schmidli H, Pirron U. Everolimus in pulmonary transplantation: pharmacokinetics and exposure-response relationships. J Heart Lung Transplant 2006;25:440-446.
48. Barnes PJ. How corticosteroids control inflammation: quintiles prize lecture 2005. Br J Pharmacol 2006;148:245-254.
49. Chen X, Murakami T, Oppenheim JJ, Howard OM. Differential response of murine CD4+CD25+ and CD4+CD25- T cells to dexamethasone-induced cell death. Eur J Immunol 2004;34:859-869.
50. Trulock EP, Christie JD, Edwards LB, Boucek MM, Aurora P, Taylor DO, Dobbels F, Rahmel AO, Keck BM, Hertz MI. Registry of the international society for heart and lung transplantation: twenty-fourth official adult lung and heart-lung transplantation report-2007. J Heart Lung Transplant 2007;26:782-795.
51. Keenan RJ, Konishi H, Kawai A, Paradis IL, Nunley DR, Iacono AT, Hardesty RL, Weyant RJ, Griffith BP. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995;60:580-584. (discussion 584-585).
52. Zuckermann A, Reichenspurner H, Birsan T, Treede H, Deviatko E, Reichart B, Klepetko W. Cyclosporine a versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial. J Thorac Cardiovasc Surg 2003;125:891-900.
53. Palmer SM, Baz MA, Sanders L, Miralles AP, Lawrence CM, Rea JB, Zander DS, Edwards LJ, Staples ED, Tapson VF, et al. Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation 2001;71:1772-1776.
54. McNeil K, Glanville AR, Wahlers T, Knoop C, Speich R, Mamelok RD, Maurer J, Ives J, Corris PA. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation 2006;81:998-1003.
55. Snell GI, Valentine VG, Vitulo P, Glanville AR, McGiffin DC, Loyd JE, Roman A, Aris R, Sole A, Hmissi A, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006;6:169-177.
56. Trulock EP, Edwards LB, Taylor DO, Boucek MM, Keck BM, Hertz MI. Registry of the international society for heart and lung transplantation: twenty-second official adult lung and heart-lung transplant report22005. J Heart Lung Transplant 2005;24:956-967.
57. Hong JC, Kahan BD. Immunosuppressive agents in organ transplantation: past, present, and future. Semin Nephrol 2000;20:108-125.
58. Caillat-Zucman S, Blumenfeld N, Legendre C, Noel LH, Bach JF, Kreis H, Chatenoud L. The OKT3 immunosuppressive effect: in situ antigenic modulation of human graft-infiltrating T cells. Transplantation 1990;49:156-160.
59. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:2715-2729.
60. Todd PA, Brogden RN. Muromonab CD3: a review of its pharmacology and therapeutic potential. Drugs 1989;37:871-899.
61. Taniguchi Y, Frickhofen N, Raghavachar A, Digel W, Heimpel H. Antilymphocyte immunoglobulins stimulate peripheral blood lymphocytes to proliferate and release lymphokines. Eur J Haematol 1990;44:244-251.
62. Merion RM, Howell T, Bromberg JS. Partial t-cell activation and anergy induction by polyclonal antithymocyte globulin. Transplantation 1998;65:1481-1489.
63. Onrust SV, Wiseman LR. Basiliximab. Drugs 1999;57:207-213. (discussion 214).
64. Wiseman LR, Faulds D. Daclizumab: a review of its use in the prevention of acute rejection in renal transplant recipients. Drugs 1999;58:1029-1042.
65. Magliocca JF, Knechtle SJ. The evolving role of alemtuzumab (campath-1h) for immunosuppressive therapy in organ transplantation. Transpl Int 2006;19:705-714.
66. Weaver TA, Kirk AD. Alemtuzumab. Transplantation 2007;84:1545-1547.
67. Cosimi AB, Colvin RB, Burton RC, Rubin RH, Goldstein G, Kung PC, Hansen WP, Delmonico FL, Russell PS. Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N Engl J Med 1981;305:308-314.
68. Renlund DG, O'Connell JB, Gilbert EM, Hammond ME, Burton NA, Jones KW, Karwande SV, Doty DB, Menlove RL, Herrick CM, et al. A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation: decreased rejection and less corticosteroid use with OKT3. Transplantation 1989;47:599-605.
69. Palmer SM, Miralles AP, Lawrence CM, Gaynor JW, Davis RD, Tapson VF. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999;116:127-133.
70. Hartwig MG, Snyder LD, Appel JZ III, Cantu E III, Lin SS, Palmer SM, Davis RD. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation. J Heart Lung Transplant 2008;27:547-553.
71. Ailawadi G, Smith PW, Oka T, Wang H, Kozower BD, Daniel TM, Kron IL, Jones DR. Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation. J Thorac Cardiovasc Surg 2008;135:594-602.
72. Hachem RR, Chakinala MM, Yusen RD, Lynch JP, Aloush AA, Patterson GA, Trulock EP. A comparison of basiliximab and antithymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant 2005;24:1320-1326.
73. Burton CM, Andersen CB, Jensen AS, Iversen M, Milman N, Boesgaard S, Arendrup H, Eliasen K, Carlsen J. The incidence of acute cellular rejection after lung transplantation: a comparative study of antithymocyte globulin and daclizumab. J Heart Lung Transplant 2006;25:638-647.
74. Mullen JC, Oreopoulos A, Lien DC, Bentley MJ, Modry DL, Stewart K, Winton TL, Jackson K, Doucette K, Preiksaitis J, et al. A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation. J Heart Lung Transplant 2007;26:504-510.
75. Brock MV, Borja MC, Ferber L, Orens JB, Anzcek RA, Krishnan J, Yang SC, Conte JV. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 2001;20:1282-1290.
76. Levine SM. A survey of clinical practice of lung transplantation in North America. Chest 2004;125:1224-1238.
77. Horning NR, Lynch JP, Sundaresan SR, Patterson GA, Trulock EP. Tacrolimus therapy for persistent or recurrent acute rejection after lung transplantation. J Heart Lung Transplant 1998;17:761-767.
78. Onsager DR, Canver CC, Jahania MS, Welter D, Michalski M, Hoffman AM, Mentzer RM Jr, Love RB. Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients. J Heart Lung Transplant 1999;18:448-455.
79. Vitulo P, Oggionni T, Cascina A, Arbustini E, D'Armini AM, Rinaldi M, Meloni F, Rossi A, Vigano M. Efficacy of tacrolimus rescue therapy in refractory acute rejection after lung transplantation. J Heart Lung Transplant 2002;21:435-439.
80. Kesten S, Chaparro C, Scavuzzo M, Gutierrez C. Tacrolimus as rescue therapy for bronchiolitis obliterans syndrome. J Heart Lung Transplant 1997;16:905-912.
81. Ross DJ, Lewis MI, Kramer M, Vo A, Kass RM. FK 506 'rescue' immunosuppression for obliterative bronchiolitis after lung transplantation. Chest 1997;112:1175-1179.
82. Sarahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville A, Chaparro C, Verleden G, Gerbase MW, Venuta F, et al. International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. J Thorac Cardiovasc Surg 2004;127:1126-1132.
83. Reams BD, Davis RD, Curl J, Palmer SM. Treatment of refractory acute rejection in a lung transplant recipient with campath 1h. Transplantation 2002;74:903-904.
84. Keenan RJ, Iacono A, Dauber JH, Zeevi A, Yousem SA, Ohori NP, Burckart GJ, Kawai A, Smaldone GC, Griffith BP. Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients. J Thorac Cardiovasc Surg 1997;113:335-340. (discussion 340-331).
85. Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006;354:141-150.
86. Diamond DA, Michalski JM, Lynch JP, Trulock EP III. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation. Int J Radiat Oncol Biol Phys 1998;41:795-800.
87. Slovis BS, Loyd JE, King LE Jr. Photopheresis for chronic rejection of lung allografts. N Engl J Med 1995;332:962.
88. Salerno CT, Park SJ, Kreykes NS, Kulick DM, Savik K, Hertz MI, Bolman RM III. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg 1999;117:1063-1069.
89. Villanueva J, Bhorade SM, Robinson JA, Husain AN, Garrity ER Jr. Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant 2000;5:44-47.
90. Lamioni A, Parisi F, Isacchi G, Giorda E, Di Cesare S, Landolfo A, Cenci F, Bottazzo GF, Carsetti R. The immunological effects of extracorporeal photopheresis unraveled: induction of tolerogenic dendritic cells in vitro and regulatory T cells in vivo. Transplantation 2005;79:846-850.