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Semin Respir Crit Care Med 2010; 31(2): 172-178
DOI: 10.1055/s-0030-1249112
© Thieme Medical Publishers

Current Trends in Immunosuppression for Lung Transplantation

Timothy Floreth1 , Sangeeta M. Bhorade1
  • 1Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago Medical Center, Chicago, Illinois
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Publication History

Publication Date:
30 March 2010 (online)

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ABSTRACT

Lung transplant has become an established therapy in the treatment of end-stage lung disease. Many of the advances in the modern immunosuppression regimen have provided more quality and quantity of life to transplant patients. Immunosuppression agents target various aspects of the immune system to maximize graft tolerance while minimizing medication toxicities and side effects. Lung transplant regimens follow typical protocols but are always tailored to the individual patient based upon previous and current medical problems. Despite the various advances, acute and chronic rejections still occur in the majority of all lung transplants. For these reasons, long-term lung transplantation success remains a challenge. Further improvement in immunosuppression will be geared toward minimizing rejection and infection as well as being tailored to the individual patient. This review details the current armamentarium of immunosuppression medications and the current body of evidence supporting the current trends of usage.

KEYWORDS

Immunosuppression - lung transplantation - induction therapy - calcineurin inhibitors - antimetabolites

REFERENCES

  • 1 Trulock E P, Christy J D, Edwards L B et al.. 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(8) 782-795
    CrossrefPubMedSearch in Google Scholar
  • 2 Trulock E P. Lung transplantation.  Am J Respir Crit Care Med. 1997;  155 789-818
    CrossrefPubMedSearch in Google Scholar
  • 3 Szczech L A, Berlin J A, Feldman H I. Anti-Lymphocyte Antibody Induction Therapy Study Group . The effect of antilymphocyte induction therapy on renal allograft survival. A meta-analysis of individual patient-level data.  Ann Intern Med. 1998;  128 817-826
    PubMedSearch in Google Scholar
  • 4 Christie J D, Edwards L B, Aurora P et al.. The Registry of the International Society for Heart and Lung Transplantation: twenty-sixth official adult lung and heart-lung transplantation report—2009.  J Heart Lung Transplant. 2009;  28(10) 1031-1049
    CrossrefPubMedSearch in Google Scholar
  • 5 Husain A N, Siddiqui M T, Holmes E W et al.. Analysis of risk factors for the development of bronchiolitis obliterans syndrome.  Am J Respir Crit Care Med. 1999;  159 829-833
    CrossrefPubMedSearch in Google Scholar
  • 6 Hachem R R, Khalifah A P, Chakinala M M et al.. The significance of a single episode of minimal acute rejection after lung transplantation.  Transplantation. 2005;  80 1406-1413
    CrossrefPubMedSearch in Google Scholar
  • 7 Hachem R R, Edwards L B, Yusen R D, Chakinala M M, Alexander Patterson G, Trulock E P. The impact of induction on survival after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry.  Clin Transplant. 2008;  22 603-608
    CrossrefPubMedSearch in Google Scholar
  • 8 Palmer S M, Miralles A P, Lawrence C M, Gaynor J W, Davis R D, Tapson V F. Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.  Chest. 1999;  116 127-133
    CrossrefPubMedSearch in Google Scholar
  • 9 Hartwig M G, Snyder L D, Appel III J Z et al.. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation.  J Heart Lung Transplant. 2008;  27 547-553
    CrossrefPubMedSearch in Google Scholar
  • 10 Moffatt S D, Demers P, Robbins R C et al.. Lung transplantation: a decade of experience.  J Heart Lung Transplant. 2005;  24 145-151
    CrossrefPubMedSearch in Google Scholar
  • 11 Hachem R R, Chakinala M M, Yusen R D et al.. A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation.  J Heart Lung Transplant. 2005;  24 1320-1326
    CrossrefPubMedSearch in Google Scholar
  • 12 Burton C M, Andersen C B, Jensen A S 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;  25 638-647
    CrossrefPubMedSearch in Google Scholar
  • 13 Mullen J C, Oreopoulos A, Lien D C et al.. A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation.  J Heart Lung Transplant. 2007;  26 504-510
    CrossrefPubMedSearch in Google Scholar
  • 14 Garrity Jr E R, Villanueva J, Bhorade S M, Husain A N, Vigneswaran W T. Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody.  Transplantation. 2001;  71 773-777
    CrossrefPubMedSearch in Google Scholar
  • 15 Levine S M. Transplant/Immunology Network of the American College of Chest Physicians . A survey of clinical practice of lung transplantation in North America.  Chest. 2004;  125 1224-1238
    CrossrefPubMedSearch in Google Scholar
  • 16 Karin M. New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?.  Cell. 1998;  93 487-490
    CrossrefPubMedSearch in Google Scholar
  • 17 Rhen T, Cidlowski J A. Antiinflammatory action of glucocorticoids—new mechanisms for old drugs.  N Engl J Med. 2005;  353 1711-1723
    CrossrefPubMedSearch in Google Scholar
  • 18 Kahan B D. Cyclosporine: a revolution in transplantation.  Transplant Proc. 1999;  31(1–2A) 14S-15S
    PubMedSearch in Google Scholar
  • 19 Iversen M, Nilsson F, Sipponen J et al.. Cyclosporine C2 levels have impact on incidence of rejection in de novo lung but not heart transplant recipients: the NOCTURNE study.  J Heart Lung Transplant. 2009;  28 919-926
    CrossrefPubMedSearch in Google Scholar
  • 20 Glanville A R, Aboyoun C L, Morton J M, Plit M, Malouf M A. Cyclosporine C2 target levels and acute cellular rejection after lung transplantation.  J Heart Lung Transplant. 2006;  25 928-934
    CrossrefPubMedSearch in Google Scholar
  • 21 Glanville A R, Morton J M, Aboyoun C L, Plit M L, Malouf M A. Cyclosporine C2 monitoring improves renal dysfunction after lung transplantation.  J Heart Lung Transplant. 2004;  23 1170-1174
    CrossrefPubMedSearch in Google Scholar
  • 22 Petric R, Freeman D, Wallace C, McDonald J, Stiller C, Keown P. Effect of cyclosporine on urinary prostanoid excretion, renal blood flow, and glomerulotubular function.  Transplantation. 1988;  45 883-889
    CrossrefPubMedSearch in Google Scholar
  • 23 Schreiber S L, Liu J, Albers M W et al.. Immunophilin-ligand complexes as probes of intracellular signaling pathways.  Transplant Proc. 1991;  23 2839-2844
    PubMedSearch in Google Scholar
  • 24 Garrity Jr E R, Hertz M I, Trulock E P, Keenan R, Love R. Suggested guidelines for the use of tacrolimus in lung-transplant recipients.  J Heart Lung Transplant. 1999;  18 175-176
    CrossrefPubMedSearch in Google Scholar
  • 25 Keenan R J, Konishi H, Kawai A et al.. Clinical trial of tacrolimus versus cyclosporine in lung transplantation.  Ann Thorac Surg. 1995;  60 580-584 discussion 584-585
    CrossrefPubMedSearch in Google Scholar
  • 26 Treede H, Klepetko W, Reichenspurner H Munich and Vienna Lung Transplant Group 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;  20 511-517
    CrossrefPubMedSearch in Google Scholar
  • 27 Hachem R R, Yusen R D, Chakinala M M et al.. A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation.  J Heart Lung Transplant. 2007;  26 1012-1018
    CrossrefPubMedSearch in Google Scholar
  • 28 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;  125 891-900
    CrossrefPubMedSearch in Google Scholar
  • 29 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 110 patients.  J Heart Lung Transplant. 2003;  22 S77
    PubMedSearch in Google Scholar
  • 30 Zuckermann A, Richensperner J, Jaksch P et al.. Long term follow-up of a prospective randomized trial comparing tacrolimus versus cyclosporine in combination with MMF after lung transplantation.  J Heart Lung Transplant. 2003;  22 S76-S77
    PubMedSearch in Google Scholar
  • 31 Hertz M I, Aurora P, Christie J D et al.. Registry of the International Society for Heart and Lung Transplantation: a quarter century of thoracic transplantation.  J Heart Lung Transplant. 2008;  27 937-942
    CrossrefPubMedSearch in Google Scholar
  • 32 Franklin T J, Cook J M. The inhibition of nucleic acid synthesis by mycophenolic acid.  Biochem J. 1969;  113 515-524
    PubMedSearch in Google Scholar
  • 33 Morris R E, Hoyt E G, Murphy M P, Eugui E M, Allison A C. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis.  Transplant Proc. 1990;  22 1659-1662
    PubMedSearch in Google Scholar
  • 34 Kobashigawa J A, Renlund D G, Gerosa G ERL2401 Heart Study Investigators 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
    CrossrefPubMedSearch in Google Scholar
  • 35 Budde K, Curtis J, Knoll G ERL B302 Study Group et al. 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
    CrossrefPubMedSearch in Google Scholar
  • 36 McNeil K, Glanville A R, Wahlers T et al.. Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients.  Transplantation. 2006;  81 998-1003
    CrossrefPubMedSearch in Google Scholar
  • 37 Lai J H, Tan T H. CD28 signaling causes a sustained down-regulation of I kappa B alpha which can be prevented by the immunosuppressant rapamycin.  J Biol Chem. 1994;  269 30077-30080
    PubMedSearch in Google Scholar
  • 38 King-Biggs M B, Dunitz J M, Park S J, Kay Savik S, Hertz M I. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation.  Transplantation. 2003;  75 1437-1443
    CrossrefPubMedSearch in Google Scholar
  • 39 McWilliams T J, Levvey B J, Russell P A, Milne D G, Snell G I. Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation.  J Heart Lung Transplant. 2003;  22 210-213
    CrossrefPubMedSearch in Google Scholar
  • 40 Snell G I, Levvey B J, Chin W et al.. Rescue therapy: a role for sirolimus in lung and heart transplant recipients.  Transplant Proc. 2001;  33 1084-1085
    CrossrefPubMedSearch in Google Scholar
  • 41 Snell G I, Valentine V G, Vitulo P RAD B159 Study Group et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.  Am J Transplant. 2006;  6 169-177
    CrossrefPubMedSearch in Google Scholar
  • 42 Valentine V G, Robbins R C, Wehner J H, Patel H R, Berry G J, Theodore J. Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts.  Chest. 1996;  109 1184-1189
    CrossrefPubMedSearch in Google Scholar
  • 43 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;  144 224-226
    PubMedSearch in Google Scholar
  • 44 Iacono A T, Smaldone G C, Keenan R J et al.. Dose-related reversal of acute lung rejection by aerosolized cyclosporine.  Am J Respir Crit Care Med. 1997;  155 1690-1698
    PubMedSearch in Google Scholar
  • 45 Reams B D, Davis R D, Curl J, Palmer S M. Treatment of refractory acute rejection in a lung transplant recipient with campath 1H.  Transplantation. 2002;  74 903-904
    CrossrefPubMedSearch in Google Scholar
  • 46 Banner N R, Rose M L, Cummins D et al.. Management of an ABO-incompatible lung transplant.  Am J Transplant. 2004;  4 1192-1196
    CrossrefPubMedSearch in Google Scholar
  • 47 Sarahrudi 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 1126-1132
    CrossrefPubMedSearch in Google Scholar
  • 48 Yates B, Murphy D M, Forrest I A et al.. Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome.  Am J Respir Crit Care Med. 2005;  172 772-775
    CrossrefPubMedSearch in Google Scholar
  • 49 Redmund K F, Guo Z, Rechsteiner T et al.. Clarithromycin has a preventative effect on chronic rejection by downregulation of innate immunity and mesenchymal growth.  J Heart Lung Transplant. 2005;  24 S144
    PubMedSearch in Google Scholar
  • 50 Tateda K, Comte R, Pechere J C, Köhler T, Yamaguchi K, Van Delden C. Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa .  Antimicrob Agents Chemother. 2001;  45 1930-1933
    CrossrefPubMedSearch in Google Scholar
  • 51 Yamasawa H, Oshikawa K, Ohno S, Sugiyama Y. Macrolides inhibit epithelial cell-mediated neutrophil survival by modulating granulocyte macrophage colony-stimulating factor release.  Am J Respir Cell Mol Biol. 2004;  30 569-575
    CrossrefPubMedSearch in Google Scholar
  • 52 Johnson B A, Iacono A T, Zeevi A, McCurry K R, Duncan S R. Statin use is associated with improved function and survival of lung allografts.  Am J Respir Crit Care Med. 2003;  167 1271-1278
    CrossrefPubMedSearch in Google Scholar
  • 53 Murphy D M, Forrest I A, Corris P A et al.. Simvastatin attenuates release of neutrophilic and remodeling factors from primary bronchial epithelial cells derived from stable lung transplant recipients.  Am J Physiol Lung Cell Mol Physiol. 2008;  294 L592-L599
    CrossrefPubMedSearch in Google Scholar
  • 54 Fisher A J, Rutherford R M, Bozzino J, Parry G, Dark J H, Corris P A. The safety and efficacy of total lymphoid irradiation in progressive bronchiolitis obliterans syndrome after lung transplantation.  Am J Transplant. 2005;  5 537-543
    CrossrefPubMedSearch in Google Scholar
  • 55 Novick R J, Kaye M P, Patterson G A et al.. Redo lung transplantation: a North American–European experience.  J Heart Lung Transplant. 1993;  12(1 Pt 1) 5-15 discussion 15-16
    PubMedSearch in Google Scholar

Sangeeta M BhoradeM.D. 

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago Medical Center

5841 S. Maryland Ave., MC 0999, Chicago, IL 60637

Email: sbhorade@medicine.bsd.uchicago.edu