Evolving Immunosuppressive Regimens for Lung Transplant Recipients

ABSTRACT

In organ transplantation, the key tenet remains the maintenance of graft function through the induction of allograft tolerance. Immunosuppression has been the mainstay of therapy to maintain graft function and induce tolerance. Immunosuppression for lung transplant and indeed all solid organ transplantation has greatly evolved in the past decade. Although calcineurin inhibitors, corticosteroids, and azathioprine remain the foundation of immunosuppression in lung transplantation, the arsenal of effective immunosuppression is ever expanding to include biological agents and newer drugs that are directed against increasingly specific targets of the immune cascade. This review examines the characteristics of both traditional and new pharmacological agents, describes a patient-centered approach to their use following lung transplantation, and discusses the controversies surrounding immunosuppression in the lung transplant recipient.

Immunosuppression - lung transplantation - calcineurin inhibitors - mammalian target of rapamycin - induction therapy

REFERENCES

• 1 Levine S M. A survey of clinical practice of lung transplantation in North America.  Chest. 2004;  125 1224-1238
• 2 Rhen T, Cidlowski J A. Antiinflammatory action of glucocorticoids: new mechanisms for old drugs.  N Engl J Med. 2005;  353 1711-1723
• 3 Karin M. New twists in gene regulation by glucocorticoid receptor: is DNA binding dispensable?.  Cell. 1998;  93 487-490
• 4 Silverborn M, Jeppsson A, Martensson G, Nilsson F. New-onset cardiovascular risk factors in lung transplant recipients.  J Heart Lung Transplant. 2005;  24 1536-1543
• 5 Elion G B. The purine path to chemotherapy.  Science. 1989;  244 41-47
• 6 Poppe D, Tiede I, Fritz G 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
• 7 Tiede I, Fritz G, Strand S 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
• 8 Palmer S M, Baz M A, 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 1772-1776
• 9 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
• 10 Buell J F, Gross T G, Woodle E S. Malignancy after transplantation.  Transplantation. 2005;  80(Suppl 2) S254-S264
• 11 Kahan B D. Cyclosporine: a revolution in transplantation.  Transplant Proc. 1999;  31(1-2A) 14S-15S
• 12 Ahsan N, Johnson C, Gonwa T et al.. Randomized trial of tacrolimus plus mycophenolate mofetil or azathioprine versus cyclosporine oral solution (modified) plus mycophenolate mofetil after cadaveric kidney transplantation: results at 2 years.  Transplantation. 2001;  72 245-250
• 13 Meier-Kriesche H U, Kaplan B. Cyclosporine microemulsion and tacrolimus are associated with decreased chronic allograft failure and improved long-term graft survival as compared with sandimmune.  Am J Transplant. 2002;  2 100-104
• 14 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
• 15 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 two-center prospective randomized trial.  J Thorac Cardiovasc Surg. 2003;  125 891-900
• 16 Kesten S, Chaparro C, Scavuzzo M, Gutierrez C. Tacrolimus as rescue therapy for bronchiolitis obliterans syndrome.  J Heart Lung Transplant. 1997;  16 905-912
• 17 Mentzer Jr R M, Jahania M S, Lasley R D. Tacrolimus as a rescue immunosuppressant after heart and lung transplantation. The US. Multicenter FK506 Study Group.  Transplantation. 1998;  65 109-113
• 18 Lipson D A, Palevsky H I, Kotloff R M, Edelman J. Conversion to tacrolimus (FK506) from cyclosporine after orthotopic lung transplantation.  Transplant Proc. 1998;  30 1505-1507
• 19 Wiebe K, Harringer W, Franke U et al.. FK506 rescue therapy in lung transplantation.  Transplant Proc. 1998;  30 1508-1509
• 20 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
• 21 Keenan R J, Duncan A J, Yousem S A et al.. Improved immunosuppression with aerosolized cyclosporine in experimental pulmonary transplantation.  Transplantation. 1992;  53 20-25
• 22 Keenan R J, Iacono A, Dauber J H et al.. Treatment of refractory acute allograft rejection with aerosolized cyclosporine in lung transplant recipients.  J Thorac Cardiovasc Surg. 1997;  113 335-340 discussion 340-341
• 23 Iacono A T, Corcoran T E, Griffith B P et al.. Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans.  Eur Respir J. 2004;  23 384-390
• 24 Iacono A T, Johnson B A, Grgurich W F et al.. A randomized trial of inhaled cyclosporine in lung-transplant recipients.  N Engl J Med. 2006;  354 141-150
• 25 Halloran P F. Immunosuppressive drugs for kidney transplantation.  N Engl J Med. 2004;  351 2715-2729
• 26 Akhlaghi F, Gonzalez L, Trull A K. Association between cyclosporine concentrations at 2 hours post-dose and clinical outcomes in de novo lung transplant recipients.  J Heart Lung Transplant. 2005;  24 2120-2128
• 27 Knoop C, Thiry P, Saint-Marcoux F, Rousseau A, Marquet P, Estenne M. Tacrolimus pharmacokinetics and dose monitoring after lung transplantation for cystic fibrosis and other conditions.  Am J Transplant. 2005;  5 1477-1482
• 28 Ragette R, Kamler M, Weinreich G, Teschler H, Jakob H. Tacrolimus pharmacokinetics in lung transplantation: new strategies for monitoring.  J Heart Lung Transplant. 2005;  24 1315-1319
• 29 Sehgal S N. Sirolimus: its discovery, biological properties, and mechanism of action.  Transplant Proc. 2003;  35(Suppl 3) 7S-14S
• 30 Brown E J, Albers M W, Shin T B et al.. A mammalian protein targeted by G1-arresting rapamycin-receptor complex.  Nature. 1994;  369 756-758
• 31 Dumont F J, Melino M R, Staruch M J, Koprak S L, Fischer P A, Sigal N H. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells.  J Immunol. 1990;  144 1418-1424
• 32 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
• 33 Flanagan W M, Crabtree G R. Rapamycin inhibits p34cdc2 expression and arrests T lymphocyte proliferation at the G1/S transition.  Ann NY Acad Sci. 1993;  696 31-37
• 34 Kim H S, Raskova J, Degiannis D, Raska Jr K. Effects of cyclosporine and rapamycin on immunoglobulin production by preactivated human B cells.  Clin Exp Immunol. 1994;  96 508-512
• 35 Marx S O, Jayaraman T, Go L O, Marks A R. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells.  Circ Res. 1995;  76 412-417
• 36 Poon M, Marx S O, Gallo R, Badimon J J, Taubman M B, Marks A R. Rapamycin inhibits vascular smooth muscle cell migration.  J Clin Invest. 1996;  98 2277-2283
• 37 Marx S O, Marks A R. Bench to bedside: the development of rapamycin and its application to stent restenosis.  Circulation. 2001;  104 852-855
• 38 Kahan B D. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group.  Lancet. 2000;  356 194-202
• 39 Kreis H, Cisterne J M, Land W et al.. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients.  Transplantation. 2000;  69 1252-1260
• 40 Watson C J, Friend P J, Jamieson N V et al.. Sirolimus: a potent new immunosuppressant for liver transplantation.  Transplantation. 1999;  67 505-509
• 41 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
• 42 Groetzner J, Kur F, Spelsberg F et al.. Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression.  J Heart Lung Transplant. 2004;  23 632-638
• 43 Dean P G, Lund W J, Larson T S et al.. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus.  Transplantation. 2004;  77 1555-1561
• 44 Kuppahally S, Al-Khaldi A, Weisshaar D et al.. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients.  Am J Transplant. 2006;  6(5 Pt 1) 986-992
• 45 Nair R V, Huang X, Shorthouse R et al.. Antiproliferative effect of rapamycin on growth factor-stimulated human adult lung fibroblasts in vitro may explain its superior efficacy for prevention and treatment of allograft obliterative airway disease in vivo.  Transplant Proc. 1997;  29 614-615
• 46 Fahrni J A, Berry G J, Morris R E, Rosen G D. Rapamycin inhibits development of obliterative airway disease in a murine heterotopic airway transplant model.  Transplantation. 1997;  63 533-537
• 47 Cahill B C, Somerville K T, Crompton J A et al.. Early experience with sirolimus in lung transplant recipients with chronic allograft rejection.  J Heart Lung Transplant. 2003;  22 169-176
• 48 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
• 49 Ussetti P, Laporta R, de Pablo A, Carreno C, Segovia J, Pulpon L. Rapamycin in lung transplantation: preliminary results.  Transplant Proc. 2003;  35 1974-1977
• 50 Groetzner J, Wittwer T, Kaczmarek I et al.. Conversion to sirolimus and mycophenolate can attenuate the progression of bronchiolitis obliterans syndrome and improves renal function after lung transplantation.  Transplantation. 2006;  81 355-360
• 51 Fritsche L, Budde K, Dragun D, Einecke G, Diekmann F, Neumayer H H. Testosterone concentrations and sirolimus in male renal transplant patients.  Am J Transplant. 2004;  4 130-131
• 52 Gonwa T, Mendez R, Yang H C, Weinstein S, Jensik S, Steinberg S. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months.  Transplantation. 2003;  75 1213-1220
• 53 Pham P T, Pham P C, Danovitch G M et al.. Sirolimus-associated pulmonary toxicity.  Transplantation. 2004;  77 1215-1220
• 54 Chhajed P N, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M. Patterns of pulmonary complications associated with sirolimus.  Respiration. 2005;  73 367-379
• 55 Champion L, Stern M, Israel-Biet D et al.. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients.  Ann Intern Med. 2006;  144 505-509
• 56 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
• 57 Rehm B, Keller F, Mayer J, Stracke S. Resolution of sirolimus-induced pneumonitis after conversion to everolimus.  Transplant Proc. 2006;  38 711-713
• 58 Eisen H J, Tuzcu E M, Dorent R et al.. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.  N Engl J Med. 2003;  349 847-858
• 59 Snell G I, Valentine V G, Vitulo P et al.. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial.  Am J Transplant. 2006;  6 169-177
• 60 Valentine V G, Love R B, Snell G I, Vitulo P, Glanville A, Pirron U. Everolimus (RAD) shows superiority over azathioprine to inhibit the decline of pulmonary function in stable lung transplant recipients - 24-month results of a multicenter, randomized, double-blind study [abstract].  Am J Transplant. 2004;  79(Suppl 8) 403
• 61 Trulock E P, Edwards L B, Taylor D O, Boucek M M, Keck B M, Hertz M I. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult lung and heart-lung transplant report-2005.  J Heart Lung Transplant. 2005;  24 956-967
• 62 Cosimi A B, Cho S I, Delmonico F L, Kaplan M M, Rohrer R J, Jenkins R L. A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection.  Transplantation. 1987;  43 91-95
• 63 Cosimi A B, Colvin R B, Burton R C et al.. 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
• 64 Trofe J, Stratta R J, Egidi M F et al.. Thymoglobulin for induction or rejection therapy in pancreas allograft recipients: a single centre experience.  Clin Transplant. 2002;  16(Suppl 7) 34-44
• 65 Renlund D G, O'Connell J B, Gilbert E M 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
• 66 Hibberd P L, Snydman D R. Cytomegalovirus infection in organ transplant recipients.  Infect Dis Clin North Am. 1995;  9 863-877
• 67 Swinnen L J, Costanzo-Nordin M R, Fisher S G et al.. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients.  N Engl J Med. 1990;  323 1723-1728
• 68 Duvoux C, Pageaux G P, Vanlemmens C et al.. Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients.  Transplantation. 2002;  74 1103-1109
• 69 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
• 70 Wiebe K, Harringer W, Wahlers T et al.. ATG induction therapy and the incidence of bronchiolitis obliterans after lung transplantation: does it make a difference?.  Transplant Proc. 1998;  30 1517-1518
• 71 Gaber A O, First M R, Tesi R J et al.. Results of the double-blind, randomized, multicenter, phase III clinical trial of thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation.  Transplantation. 1998;  66 29-37
• 72 Merion R M, Howell T, Bromberg J S. Partial T-cell activation and anergy induction by polyclonal antithymocyte globulin.  Transplantation. 1998;  65 1481-1489
• 73 Basiliximab approved for use in renal transplant patients.  Am J Health Syst Pharm. 1998;  55 1444-1445
• 74 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;  342 613-619
• 75 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
• 76 Gerbase M W, de Perrot M, Spiliopoulos A, Nicod L P. Selective monoclonal versus polyclonal antibodies for induction of immunosuppression in lung recipients.  Clin Pharmacol Ther. 2002;  72 103
• 77 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
• 78 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
• 79 Brock M V, Borja M C, 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 1282-1290
• 80 Bhorade S M, Jordan A, Villanueva J et al.. Comparison of three tacrolimus-based immunosuppressive regimens in lung transplantation.  Am J Transplant. 2003;  3 1570-1575
• 81 Flynn J M, Byrd J C. Campath-1H monoclonal antibody therapy.  Curr Opin Oncol. 2000;  12 574-581
• 82 Morris P J, Russell N K. Alemtuzumab (Campath-1H): a systematic review in organ transplantation.  Transplantation. 2006;  81 1361-1367
• 83 McCurry K R, Iacono A, Zeevi A et al.. Early outcomes in human lung transplantation with thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy.  J Thorac Cardiovasc Surg. 2005;  130 528-537
• 84 Starzl T E, Zinkernagel R M. Antigen localization and migration in immunity and tolerance.  N Engl J Med. 1998;  339 1905-1913
• 85 Trulock E P. Management of lung transplant rejection.  Chest. 1993;  103 1566-1576
• 86 Yousem S A, Berry G J, Cagle P T et al.. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group.  J Heart Lung Transplant. 1996;  15(1 Pt 1) 1-15
• 87 Guilinger R A, Paradis I L, Dauber J H et al.. The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients.  Am J Respir Crit Care Med. 1995;  152(6 Pt 1) 2037-2043
• 88 Diamond D A, Michalski J M, Lynch J P, Trulock III E P. Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation.  Int J Radiat Oncol Biol Phys. 1998;  41 795-800
• 89 Andreu G, Achkar A, Couetil J P et al.. Extracorporeal photochemotherapy treatment for acute lung rejection episode.  J Heart Lung Transplant. 1995;  14 793-796
• 90 Wise B V, King K E, Rook A H, Mogayzel Jr P J. Extracorporeal photopheresis in the treatment of persistent rejection in a pediatric lung transplant recipient.  Prog Transplant. 2003;  13 61-64
• 91 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
• 92 Suzuki H, Shimomura A, Ikeda K, Furukawa M, Oshima T, Takasaka T. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells.  Laryngoscope. 1997;  107(12 Pt 1) 1661-1666
• 93 Ianaro A, Ialenti A, Maffia P et al.. Anti-inflammatory activity of macrolide antibiotics.  J Pharmacol Exp Ther. 2000;  292 156-163
• 94 Elssner A, Jaumann F, Dobmann S et al.. Elevated levels of interleukin-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant Group.  Transplantation. 2000;  70 362-367
• 95 DiGiovine B, Lynch III J P, Martinez F J et al.. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8.  J Immunol. 1996;  157 4194-4202
• 96 Gerhardt S G, McDyer J F, Girgis R E, Conte J V, Yang S C, Orens J B. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study.  Am J Respir Crit Care Med. 2003;  168 121-125
• 97 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
• 98 Verleden G M, Dupont L J. Azithromycin therapy for patients with bronchiolitis obliterans syndrome after lung transplantation.  Transplantation. 2004;  77 1465-1467
• 99 Kobashigawa J A. Statins in solid organ transplantation: is there an immunosuppressive effect?.  Am J Transplant. 2004;  4 1013-1018
• 100 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
• 101 Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator.  Nat Med. 2000;  6 1399-1402
• 102 Palmer S M, Miralles A P, Howell D N, Brazer S R, Tapson V F, Davis R D. Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation.  Chest. 2000;  118 1214-1217
• 103 Hadjiliadis D, Duane Davis R, Steele M P et al.. Gastroesophageal reflux disease in lung transplant recipients.  Clin Transplant. 2003;  17 363-368
• 104 Davis Jr R D, Lau C L, Eubanks S et al.. Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation.  J Thorac Cardiovasc Surg. 2003;  125 533-542
• 105 Cantu III E, Appel III J Z, Hartwig M G et al.. J. Maxwell Chamberlain Memorial Paper. Early fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux disease.  Ann Thorac Surg. 2004;  78 1142-1151 discussion 1151
• 106 Massicot-Fisher J, Noel P, Madsen J C. Recommendations of the National Heart, Lung and Blood Institute Heart and Lung Tolerance Working Group.  Transplantation. 2001;  72 1467-1470
• 107 Li S, Louis IV L B, Kawaharada N, Yousem S A, Pham S M. Intrathymic inoculation of donor bone marrow induces long-term acceptance of lung allografts.  Ann Thorac Surg. 2003;  75 257-263 discussion 263