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Immunosuppression for Lung Transplantation

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Abstract

With the introduction of ciclosporin (cyclosporine) into routine clinical practice 20 years ago, lung transplantation has become an established treatment for patients with advanced lung disease. Most lung transplant recipients routinely continue to receive a triple-drug maintenance immunosuppressive regimen consisting of a calcineurin inhibitor, an antimetabolite and corticosteroids. The use of antibody-based induction therapy remains common, although there has been a shift away from T cell-depleting agents, such as antithymocyte globulin, towards anti-interleukin-2 receptor monoclonal antibodies. Recent years have seen the introduction of sirolimus and everolimus, immunosuppressive drugs that act by blocking growth factor-driven cell proliferation. While the newer immunosuppressive drugs have been rigorously evaluated in large randomised trials in kidney, liver and cardiac transplantation, such studies are lacking in lung transplantation. Despite a shift towards more potent immunosuppressive regimens that incorporate tacrolimus and mycophenolate mofetil, the development of chronic allograft rejection, as manifested by the bronchiolitis obliterans syndrome continues to negatively impact on the long-term survival of lung transplant recipients. This article reviews the evidence for the immunosuppressive regimens used during induction and maintenance of patients undergoing lung transplantation, and discusses current strategies in the management of chronic rejection.

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References

  1. Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult lung and heart-lung transplantation report, 2006. J Heart Lung Transplant 2006; 25(8): 880–92

    Article  PubMed  Google Scholar 

  2. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002; 21(3): 297–310

    Article  PubMed  Google Scholar 

  3. Trulock EP. Management of lung transplant rejection. Chest 1993; 103(5): 1566–76

    Article  PubMed  CAS  Google Scholar 

  4. Beniaminovitz A, Itescu S, Lietz K, et al. Prevention of rejection in cardiac transplantation by blockade of the interleukin-2 receptor with a monoclonal antibody. N Engl J Med 2000; 342(9): 613–9

    Article  PubMed  CAS  Google Scholar 

  5. Knoop C, Haverich A, Fischer S. Immunosuppressive therapy after human lung transplantation. Eur Respir J 2004; 23(1): 159–71

    Article  PubMed  CAS  Google Scholar 

  6. Palmer SM, Miralles AP, Lawrence CM, et al. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study. Chest 1999; 116(1): 127–33

    Article  PubMed  CAS  Google Scholar 

  7. Garrity ER Jr, Villanueva J, Bhorade SM, et al. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody. Transplantation 2001; 71(6): 773–7

    Article  PubMed  CAS  Google Scholar 

  8. Brock MV, Borja MC, Ferber L, et al. Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 2001; 20(12): 1282–90

    Article  PubMed  CAS  Google Scholar 

  9. Waddell TK, Borro JM, Roman A, et al. A double-blind randomized trial comparing basiliximab to placebo in lung transplantation [abstract]. J Heart Lung Transplant 2006; 25 (2 Suppl.): S114

    Article  Google Scholar 

  10. Hachem RR, Chakinala MM, Yusen RD, et al. A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant 2005; 24(9): 1320–6

    Article  PubMed  Google Scholar 

  11. Burton CM, Andersen CB, Jensen AS, et al. The incidence of acute cellular rejection after lung transplantation: a comparative study of anti-thymocyte globulin and daclizumab. J Heart Lung Transplant 2006; 25(6): 638–47

    Article  PubMed  Google Scholar 

  12. US National Institutes of Health. Study of EZ-2053 in the prophylaxis of acute pulmonary allograft rejection [online]. Available from URL: http://clinicaltrials.gov/ct/show/NCT00105183?order=22[Accessed 2007 19 Jun]

  13. Borro JM, Sole A, De la Torre M, et al. Steroid withdrawal in lung transplant recipients. Transplant Proc 2005; 37(9): 3991–3

    Article  PubMed  CAS  Google Scholar 

  14. Borel JF, Feurer C, Gubler HU, et al. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 1976; 6(4): 468–75

    Article  PubMed  CAS  Google Scholar 

  15. Trull A, Steel L, Sharpies L, et al. Randomized, trough blood cyclosporine concentration-controlled trial to compare the pharmacodynamics of Sandimmune and Neoral in de novo lung transplant recipients. Ther Drug Monit 1999; 21(1): 17–26

    Article  PubMed  CAS  Google Scholar 

  16. Glanville AR, Aboyoun CL, Morton JM, et al. Cyclosporine C2 target levels and acute cellular rejection after lung transplantation. J Heart Lung Transplant 2006; 25(8): 928–34

    Article  PubMed  Google Scholar 

  17. Goto T, Kino T, Hatanaka H, et al. FK 506: historical perspectives. Transplant Proc 1991; 23(6): 2713–7

    PubMed  CAS  Google Scholar 

  18. Schreiber SL, Liu J, Albers MW, et al. Immunophilin-ligand complexes as probes of intracellular signaling pathways. Transplant Proc 1991; 23(6): 2839–44

    PubMed  CAS  Google Scholar 

  19. Garrity ER Jr, Hertz MI, Trulock EP, et al. Suggested guidelines for the use of tacrolimus in lung-transplant recipients. J Heart Lung Transplant 1999; 18(3): 175–6

    Article  PubMed  Google Scholar 

  20. Reichenspurner H, Kur F, Treede H, et al. Optimization of the immunosuppressive protocol after lung transplantation. Transplantation 1999; 68(1): 67–71

    Article  PubMed  CAS  Google Scholar 

  21. Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995; 60(3): 580–4; discussion 584-5

    Article  PubMed  CAS  Google Scholar 

  22. Treede H, Klepetko W, Reichenspurner H, et al. Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant 2001; 20(5): 511–7

    Article  PubMed  CAS  Google Scholar 

  23. Reichenspurner H, Glanville A, Klepetko W, et al. Prospective randomized international multi-center investigator driven study comparing TAC and CSA (+MMF/steroids) after lung transplantation: interim analysis of 100 patients. J Heart Lung Transplant 2003; 22 (1 Suppl. 5): S77

    Article  Google Scholar 

  24. Zuckermann A, Reichenspurner H, Jaksch P, et al. Long term follow-up of a prospective randomized trial comparing tacrolimus versus cyclosporine in combination with MMF after lung transplantation [abstract]. J Heart Lung Transplant 2003; 22: S26

    Article  Google Scholar 

  25. Zuckermann A, Reichenspurner H, Birsan T, et al. 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(4): 891–900

    Article  PubMed  CAS  Google Scholar 

  26. Sarahradi K, Estenne M, Corris P, et al. International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. J Thorac Cardiovasc Surg 2004; 127(4): 1126–32

    Article  Google Scholar 

  27. Van Gelder T, Klupp J, Barten MJ, et al. Co-administration of tacrolimus and mycophenolate mofetil does not increase mycophenolic acid (MPA) exposure, but co-administration of cyclosporine inhibits the enterohepatic recirculation of MPA, thereby decreasing its exposure. J Heart Lung Transplant 2001; 20(2): 160–1

    Article  PubMed  Google Scholar 

  28. Kahan BD, Keown P, Levy GA, et al. Therapeutic drag monitoring of immunosuppressant drugs in clinical practice. Clin Ther 2002; 24(3): 330–50; discussion 329

    Article  PubMed  CAS  Google Scholar 

  29. Ross DJ, Waters PF, Levine M, et al. Mycophenolate mofetil versus azathioprine immunosuppressive regimens after lung transplantation: preliminary experience. J Heart Lung Transplant 1998; 17(8): 768–74

    PubMed  CAS  Google Scholar 

  30. O’Hair DP, Cantu E, McGregor C, et al. Preliminary experience with mycophenolate mofetil used after lung transplantation. J Heart Lung Transplant 1998; 17(9): 864–8

    PubMed  Google Scholar 

  31. Zuckermann A, Klepetko W, Birsan T, et al. Comparison between mycophenolate mofetil- and azathioprine-based immunosuppressions in clinical lung transplantation. J Heart Lung Transplant 1999; 18(5): 432–40

    Article  PubMed  CAS  Google Scholar 

  32. Palmer SM, Baz MA, Sanders L, 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(12): 1772–6

    Article  PubMed  CAS  Google Scholar 

  33. McNeil K, Glanville AR, Wahlers T, et al. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchioloitis obliterans syndrome in de novo lung transplant recipients. Transplantation 2006; 81(7): 998–1003

    Article  PubMed  CAS  Google Scholar 

  34. Nashan B. Review of the proliferation inhibitor everolimus. Expert Opin Investig Drags 2002; 11(12): 1845–57

    Article  CAS  Google Scholar 

  35. Azzola A, Havryk A, Chhajed P, et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation 2004; 77(2): 275–80

    Article  PubMed  CAS  Google Scholar 

  36. Salminen US, Maasilta PK, Taskinen EI, et al. Prevention of small airway obliteration in a swine heterotopic lung allograft model. J Heart Lung Transplant 2000; 19(2): 193–206

    Article  PubMed  CAS  Google Scholar 

  37. Hausen B, Boeke K, Berry GJ, et al. Suppression of acute rejection in allogeneic rat lung transplantation: a study of the efficacy and pharmacokinetics of rapamycin derivative (SDZ RAD) used alone and in combination with a microemulsion formulation of cyclosporine. J Heart Lung Transplant 1999; 18(2): 150–9

    Article  PubMed  CAS  Google Scholar 

  38. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349(9): 847–58

    Article  PubMed  CAS  Google Scholar 

  39. Vitko S, Margreiter R, Weimar W, et al. Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation 2004; 78(10): 1532–40

    Article  PubMed  Google Scholar 

  40. Snell GI, Levvey BJ, Zheng L, et al. Everolimus alters the bronchoalveolar lavage and endobronchial biopsy immunologic profile post-human lung transplantation. Am J Transplant 2005; 5(6): 1446–51

    Article  PubMed  CAS  Google Scholar 

  41. Snell GI, Valentine VG, Vitulo P, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant 2006; 6(1): 169–77

    Article  PubMed  CAS  Google Scholar 

  42. US National Institutes of Health. Immunosuppressive therapy with certican (everolimus) after lung transplantation [online]. Available from URL: http://clinicaltrials.gov/ct/show/NCT00402532?order=22 [Accessed 2007 19 Jun]

  43. Snell GI, Levvey BJ, Chin W, et al. Rescue therapy: a role for sirolimus in lung and heart transplant recipients. Transplant Proc 2001; 33 (1–2): 1084–5

    Article  Google Scholar 

  44. Snell GI, Levvey BJ, Chin W, et al. Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant 2002; 21(5): 540–6

    Article  PubMed  Google Scholar 

  45. Cahill BC, Somerville KT, Crompton JA, et al. Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. J Heart Lung Transplant 2003; 22(2): 169–76

    Article  PubMed  Google Scholar 

  46. McWilliams TJ, Levvey BJ, Russell PA, et al. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation. J Heart Lung Transplant 22(2): 210–3, 2003

    Article  PubMed  Google Scholar 

  47. King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75(9): 1437–43

    Article  PubMed  Google Scholar 

  48. US National Institutes of Health. AIRSAC trial: comparison of a tacrolimus/sirolimus/prednisone regimen versus tacrolimus/azathioprine/prednisone immunosuppressive regimen in lung transplantation [online]. Available from URL: http://clinicaltrials.gov/ct/show/NCT00321906 [Accessed 2007 19 Jun]

  49. Calverley PM. The role of corticosteroids in chronic obstructive pulmonary disease. Semin Respir Crit Care Med 2005; 26(2): 235–45

    Article  PubMed  Google Scholar 

  50. Speich R, Boehler A, Russi EW, et al. A case report of a double-blind, randomized trial of inhaled steroids in a patient with lung transplant bronchiolitis obliterans. Respiration 1997; 64(5): 375–80

    Article  PubMed  CAS  Google Scholar 

  51. Takao M, Higenbottam TW, Audley T, et al. Effects of inhaled nebulized steroids (budesonide) on acute and chronic lung function in heart-lung transplant patients. Transplant Proc 1995; 27(1): 1284–5

    PubMed  CAS  Google Scholar 

  52. Whitford H, Walters EH, Levvey B, et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002; 73(11): 1793–9

    Article  PubMed  CAS  Google Scholar 

  53. Keenan RJ, Zeevi A, Iacono AT, et al. Efficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics. Surgery 1995; 118(2): 385–91

    Article  PubMed  CAS  Google Scholar 

  54. Iacono AT, Johnson BA, Grgurich WF, et al. A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 2006; 354(2): 141–50

    Article  PubMed  Google Scholar 

  55. DeCamp MM Jr. Inhaled cyclosporine: a breath of fresh air? N Engl J Med 2006; 354(2): 191–3

    Article  PubMed  CAS  Google Scholar 

  56. Snell G, Kotsimbos T, Williams TJ. Lung transplantation in Australia: barriers to translating new evidence into clinical practice: evidence “beyond reasonable doubt” may never be achievable for low-volume drugs. Med J Aust 2006; 184(9): 428–9

    PubMed  Google Scholar 

  57. Griffith BP, Bando K, Hardesty RL, et al. A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation. Transplantation 1994; 57(6): 848–51

    Article  PubMed  CAS  Google Scholar 

  58. Homing NR, Lynch JP, Sundaresan SR, et al. Tacrolimus therapy for persistent or recurrent acute rejection after lung transplantation. J Heart Lung Transplant 1998; 17(8): 761–7

    Google Scholar 

  59. Onsager DR, Canver CC, Jahania MS, et al. Efficacy of tacrolimus in the treatment of refractory rejection in heart and lung transplant recipients. J Heart Lung Transplant 1999; 18(5): 448–55

    Article  PubMed  CAS  Google Scholar 

  60. Shennib H, Mercado M, Nguyen D, et al. Successful treatment of steroid-resistant double-lung allograft rejection with Orthoclone OKT3. Am Rev Respir Dis 1991; 144(1): 224–6

    Article  PubMed  CAS  Google Scholar 

  61. Cahill BC, O’Rourke MK, Strasburg KA, et al. Methotrexate for lung transplant recipients with steroid-resistant acute rejection. J Heart Lung Transplant 1996; 15(11): 1130–7

    PubMed  CAS  Google Scholar 

  62. Keenan RJ, Iacono A, Dauber JH, et al. Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients. J Thorac Cardiovasc Surg 1997; 113(2): 335–40; discussion 340-1

    Article  PubMed  CAS  Google Scholar 

  63. De Soyza A, Fisher AJ, Small T, et al. Inhaled corticosteroids and the treatment of lymphocytic bronchiolitis following lung transplantation. Am J Respir Crit Care Med 2001; 164(7): 1209–12

    PubMed  Google Scholar 

  64. Valentine VG, Robbins RC, Wehner JH, et al. Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts. Chest 1996; 109(5): 1184–9

    Article  PubMed  CAS  Google Scholar 

  65. Banner NR, Rose ML, Cummins D, et al. Management of an ABO-incompatible lung transplant. Am J Transplant 2004; 4(7): 1192–6

    Article  PubMed  Google Scholar 

  66. Snell GI, Esmore DS, Williams TJ. Cytolytic therapy for the bronchiolitis obliterans syndrome complicating lung transplantation. Chest 1996; 109(4): 874–8

    Article  PubMed  CAS  Google Scholar 

  67. Kesten S, Rajagopalan N, Maurer J. Cytolytic therapy for the treatment of bronchiolitis obliterans syndrome following lung transplantation. Transplantation 1996; 61(3): 427–30

    Article  PubMed  CAS  Google Scholar 

  68. Date H, Lynch JP, Sundaresan S, et al. The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 1998; 17(9): 869–75

    PubMed  CAS  Google Scholar 

  69. Dusmet M, Maurer J, Winton T, et al. Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996; 15(9): 948–54

    PubMed  CAS  Google Scholar 

  70. Verleden GM, Buyse B, Delcroix M, et al. Cyclophosphamide rescue therapy for chronic rejection after lung transplantation. J Heart Lung Transplant 1999; 18(11): 1139–42

    Article  PubMed  CAS  Google Scholar 

  71. Salerno CT, Park SJ, Kreykes NS, et al. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg 1999; 117(6): 1063–9

    Article  PubMed  CAS  Google Scholar 

  72. Diamond DA, Michalski JM, Lynch JP, et al. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation. Int J Radiat Oncol Biol Phys 1998; 41(4): 795–800

    Article  PubMed  CAS  Google Scholar 

  73. Yates B, Murphy DM, Forrest IA, et al. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2005; 172(6): 772–5

    Article  PubMed  Google Scholar 

  74. Gerhardt SG, McDyer JF, Girgis RE, et al. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003; 168(1): 121–5

    Article  PubMed  Google Scholar 

  75. Verleden GM, Dupont LJ. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2004; 77(9): 1465–7

    Article  PubMed  CAS  Google Scholar 

  76. Johnson BA, Iacono AT, Zeevi A, et al. Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003; 167(9): 1271–8

    Article  PubMed  Google Scholar 

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  1. Department of Allergy, Immunology and Respiratory Medicine, Lung Transplant Service, Alfred Hospital and Monash University, Commercial Road, Melbourne, Victoria, 3004, Australia

    Gregory I. Snell & Glen P. Westall

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  1. Gregory I. Snell
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Correspondence to Gregory I. Snell.

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Snell, G.I., Westall, G.P. Immunosuppression for Lung Transplantation. Drugs 67, 1531–1539 (2007). https://doi.org/10.2165/00003495-200767110-00002

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