Advertisement

Immunosuppression in Lung Transplantation

  • Joshua A. Blatter
  • Peter H. Michelson
Reference work entry
Part of the Organ and Tissue Transplantation book series (OTT)

Abstract

The goal of immunosuppression is to reduce the incidence of allograft rejection. Optimal immunosuppression involves minimizing side effects, such as infection and renal injury, while maximizing immune tolerance. Induction immunosuppression commonly entails systemic corticosteroids as well as an interleukin-2 receptor antagonist or a polyclonal antibody. Maintenance immunosuppression necessitates a three-drug regimen: systemic corticosteroids, as well as a calcineurin inhibitor and antimetabolite therapy (typically tacrolimus and mycophenolate mofetil). Renal side effects, both acute and chronic, are an ongoing challenge in calcineurin inhibition. Treatment of acute cellular rejection involves T-cell blockade with systemic corticosteroids. Antibody-mediated rejection treatment, on the other hand, entails the use of B-cell and antibody reduction therapies, such as intravenous immune globulin, plasmapheresis, and anti-CD20 monoclonal antibodies. Approaches to chronic rejection are even more varied, involving azithromycin, HMG coenzyme A reductase inhibitors, and extracorporeal photopheresis (a therapy in which a patient’s white blood cells undergo irradiation). Some special clinical scenarios, such as posttransplant lymphoproliferative disorder and posterior reversible encephalopathy syndrome, necessitate a reduction of maintenance immunosuppression.

Keywords

Immunosuppression Renal failure Induction Systemic corticosteroids Maintenance immunosuppression Calcineurin inhibitor Antimetabolite therapy Acute cellular rejection Antibody-mediated rejection Chronic lung allograft dysfunction (CLAD) Posttransplant lymphoproliferative disorder (PTLD) Posterior reversible encephalopathy syndrome (PRES) 

References

  1. Ahya VN, McShane PJ, Baz MA, Valentine VG, Arcasoy SM, Love RB, Seethamraju H, Garrity E, Alex CG, Bag R, DeOliveira NC, Vigneswaran WT, Charbeneau J, Krishnan JA, Durazo-Arvizu R, Norwick L, Bhorade S (2011) Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation. J Heart Lung Transplant 30(2):175–181CrossRefPubMedGoogle Scholar
  2. Ailawadi G, Smith PW, Oka T, Wang H, Kozower BD, Daniel TM, Kron IL, Jones DR (2008) Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation. J Thorac Cardiovasc Surg 135(3): 594–602CrossRefPubMedGoogle Scholar
  3. Astor TL, Weill D, Cool C, Teitelbaum I, Schwarz MI, Zamora MR (2005) Pulmonary capillaritis in lung transplant recipients: treatment and effect on allograft function. J Heart Lung Transplant 24(12):2091–2097CrossRefPubMedGoogle Scholar
  4. Barr ML, Meiser BM, Eisen HJ, Roberts RF, Livi U, Dall’Amico R, Dorent R, Rogers JG, Radovancevic B, Taylor DO, Jeevanandam V, Marboe CC (1998) Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 339(24): 1744–1751CrossRefPubMedGoogle Scholar
  5. Bayer J, Das NA, Baisden CE, Rani M, DeArmond DT, Peters JI, Johnson SB (2013) Effect of inhaled tacrolimus on ischemia reperfusion injury in rat lung transplant model. J Thorac Cardiovasc Surg 146(5): 1213–1219; discussion 1219CrossRefPubMedGoogle Scholar
  6. Behrend M (2001) Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf 24(9):645–663CrossRefPubMedGoogle Scholar
  7. Borro JM, Sole A, De la Torre M, Pastor A, Tarazona V (2005) Steroid withdrawal in lung transplant recipients. Transplant Proc 37(9):3991–3993CrossRefPubMedGoogle Scholar
  8. Brock MV, Borja MC, Ferber L, Orens JB, Anzcek RA, Krishnan J, Yang SC, Conte JV (2001) Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 20(12): 1282–1290CrossRefPubMedGoogle Scholar
  9. Burton CM, Andersen CB, Jensen AS, Iversen M, Milman N, Boesgaard S, Arendrup H, Eliasen K, Carlsen J (2006) The incidence of acute cellular rejection after lung transplantation: a comparative study of anti-thymocyte globulin and daclizumab. J Heart Lung Transplant 25(6):638–647CrossRefPubMedGoogle Scholar
  10. Bustami RT, Ojo AO, Wolfe RA, Merion RM, Bennett WM, McDiarmid SV, Leichtman AB, Held PJ, Port FK (2017) Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 4(1):87–93CrossRefGoogle Scholar
  11. Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M (2014) Diagnosis and management of antibody-mediated rejection: current status and novel approaches. Am J Transplant 14(2):255–271CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dosanjh AK, Wan B, Throndset W, Sherwood S, Morris RE (1998) Pirfenidone: a novel antifibrotic agent with implications for the treatment of obliterative bronchiolitis. Transplant Proc 30(5):1910–1911CrossRefPubMedGoogle Scholar
  13. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF, Study EL-S (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357(25):2562–2575CrossRefPubMedGoogle Scholar
  14. European FK506 Multicentre Liver Study Group (1994) Randomised trial comparing tacrolimus (FK506) and cyclosporin in prevention of liver allograft rejection. European FK506 Multicentre Liver Study Group. Lancet 344(8920):423–428CrossRefGoogle Scholar
  15. Fan Y, Xiao YB, Weng YG (2009) Tacrolimus versus cyclosporine for adult lung transplant recipients: a meta-analysis. Transplant Proc 41(5):1821–1824CrossRefPubMedGoogle Scholar
  16. Furuya Y, Jayarajan SN, Taghavi S, Cordova FC, Patel N, Shiose A, Leotta E, Criner GJ, Guy TS, Wheatley GH, Kaiser LR, Toyoda Y (2016) The impact of Alemtuzumab and Basiliximab induction on patient survival and time to bronchiolitis obliterans syndrome in double lung transplantation recipients. Am J Transplant 16(8):2334–2341CrossRefPubMedGoogle Scholar
  17. Galiwango PJ, Delgado DH, Yan R, Kozuszko S, Smith R, Rao V, Ross HJ (2008) Mycophenolate mofetil dose reduction for gastrointestinal intolerance is associated with increased rates of rejection in heart transplant patients. J Heart Lung Transplant 27(1):72–77CrossRefPubMedGoogle Scholar
  18. Gerbase MW, Fathi M, Spiliopoulos A, Rochat T, Nicod LP (2003) Pharmacokinetics of mycophenolic acid associated with calcineurin inhibitors: long-term monitoring in stable lung recipients with and without cystic fibrosis. J Heart Lung Transplant 22(5):587–590CrossRefPubMedGoogle Scholar
  19. Goldfarb SB, Levvey BJ, Edwards LB, Dipchand AI, Kucheryavaya AY, Lund LH, Meiser B, Rossano JW, Yusen RD, Stehlik J, International Society for Heart and Lung Transplantation (2016) The registry of the International Society for Heart and Lung Transplantation: nineteenth pediatric lung and heart-lung transplantation Report-2016; Focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant 35(10):1196–1205CrossRefPubMedGoogle Scholar
  20. Greenway SC, Butts R, Naftel DC, Pruitt E, Kirklin JK, Larsen I, Urschel S, Knecht K, Law Y (2016) Statin therapy is not associated with improved outcomes after heart transplantation in children and adolescents. J Heart Lung Transplant 35(4):457–465CrossRefPubMedGoogle Scholar
  21. Greer M, Dierich M, De Wall C, Suhling H, Rademacher J, Welte T, Haverich A, Warnecke G, Ivanyi P, Buchholz S, Gottlieb J, Fuehner T (2013) Phenotyping established chronic lung allograft dysfunction predicts extracorporeal photopheresis response in lung transplant patients. Am J Transplant 13(4):911–918CrossRefPubMedGoogle Scholar
  22. Hachem RR, Chakinala MM, Yusen RD, Lynch JP, Aloush AA, Patterson GA, Trulock EP (2005) A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant 24(9):1320–1326CrossRefPubMedGoogle Scholar
  23. Hachem RR, Yusen RD, Chakinala MM, Meyers BF, Lynch JP, Aloush AA, Patterson GA, Trulock EP (2007) A randomized controlled trial of tacrolimus versus cyclosporine after lung transplantation. J Heart Lung Transplant 26(10):1012–1018CrossRefPubMedGoogle Scholar
  24. Hachem RR, Edwards LB, Yusen RD, Chakinala MM, Alexander Patterson G, Trulock EP (2008) The impact of induction on survival after lung transplantation: an analysis of the International Society for Heart and Lung Transplantation Registry. Clin Transpl 22(5):603–608CrossRefGoogle Scholar
  25. Hachem RR, Yusen RD, Meyers BF, Aloush AA, Mohanakumar T, Patterson GA, Trulock EP (2010) Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation. J Heart Lung Transplant 29(9):973–980CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hardinger KL, Schnitzler MA, Miller B, Lowell JA, Shenoy S, Koch MJ, Enkvetchakul D, Ceriotti C, Brennan DC (2004) Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation 78(1):136–141CrossRefPubMedGoogle Scholar
  27. Hardy JD, Webb WR, Dalton ML, Walker GR (1963) Lung homotransplantation in man: report of the initial case. JAMA 186(12):1065–1074CrossRefPubMedGoogle Scholar
  28. Hayes D Jr, Kirkby S, Wehr AM, Lehman AM, McConnell PI, Galantowicz M, Higgins RS, Whitson BA (2014) A contemporary analysis of induction immunosuppression in pediatric lung transplant recipients. Transpl Int 27(2):211–218CrossRefPubMedGoogle Scholar
  29. Helderman JH, Goral S (2002) Gastrointestinal complications of transplant immunosuppression. J Am Soc Nephrol 13(1):277–287PubMedGoogle Scholar
  30. Hinchey J, Chaves C, Appignani B, Breen J, Pao L, Wang A, Pessin MS, Lamy C, Mas JL, Caplan LR (1996) A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334(8):494–500CrossRefPubMedGoogle Scholar
  31. Hui C, Kern R, Wojciechowski D, Kukreja J, Golden JA, Hays SR, Singer JP (2014) Belatacept for maintenance immunosuppression in lung transplantation. J Invest Med High Impact Case Rep 2(3):2324709614546866Google Scholar
  32. Iacono AT, Johnson BA, Grgurich WF, Youssef JG, Corcoran TE, Seiler DA, Dauber JH, Smaldone GC, Zeevi A, Yousem SA, Fung JJ, Burckart GJ, McCurry KR, Griffith BP (2006) A randomized trial of inhaled cyclosporine in lung-transplant recipients. N Engl J Med 354(2):141–150CrossRefPubMedGoogle Scholar
  33. Jacobson PA, Oetting WS, Brearley AM, Leduc R, Guan W, Schladt D, Matas AJ, Lamba V, Julian BA, Mannon RB, Israni A, DeKAF Investigators (2011) Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation 91(3): 300–308CrossRefPubMedPubMedCentralGoogle Scholar
  34. Jaksch P, Scheed A, Keplinger M, Ernst MB, Dani T, Just U, Nahavandi H, Klepetko W, Knobler R (2012) A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 31(9):950–957CrossRefPubMedGoogle Scholar
  35. Johnson B, Iacono A, Zeevi A, McCurry K, Duncan S (2003) Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 167(9):1271–1278CrossRefPubMedGoogle Scholar
  36. Kamel KS, Ethier JH, Quaggin S, Levin A, Albert S, Carlisle EJ, Halperin ML (1992) Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. J Am Soc Nephrol 2(8):1279–1284PubMedGoogle Scholar
  37. Keenan RJ, Konishi H, Kawai A, Paradis IL, Nunley DR, Iacono AT, Hardesty RL, Weyant RJ, Griffith BP (1995a) Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 60(3): 580–584; discussion 584–585CrossRefPubMedGoogle Scholar
  38. Keenan RJ, Zeevi A, Iacono AT, Spichty KJ, Cai JZ, Yousem SA, Ohori NP, Paradis IL, Kawai A, Griffith BP (1995b) Efficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics. Surgery 118(2):385–391CrossRefPubMedGoogle Scholar
  39. Lennard L, Van Loon JA, Weinshilboum RM (1989) Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 46(2):149–154CrossRefPubMedGoogle Scholar
  40. MacPhee IA, Spreafico S, Bewick M, Davis C, Eastwood JB, Johnston A, Lee T, Holt DW (2000) Pharmacokinetics of mycophenolate mofetil in patients with end-stage renal failure. Kidney Int 57(3): 1164–1168CrossRefPubMedGoogle Scholar
  41. McManigle W, Pavlisko EN, Martinu T (2013) Acute cellular and antibody-mediated allograft rejection. Semin Respir Crit Care Med 34(3):320–335CrossRefPubMedGoogle Scholar
  42. McNeil K, Glanville AR, Wahlers T, Knoop C, Speich R, Mamelok RD, Maurer J, Ives J, Corris PA (2006) Comparison of mycophenolate mofetil and azathioprine for prevention of bronchiolitis obliterans syndrome in de novo lung transplant recipients. Transplantation 81(7):998–1003CrossRefPubMedGoogle Scholar
  43. Medawar PB (1944) The behaviour and fate of skin autografts and skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. J Anat 78(Pt 5):176–199PubMedPubMedCentralGoogle Scholar
  44. Morrell MR, Despotis GJ, Lublin DM, Patterson GA, Trulock EP, Hachem RR (2010) The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 29(4): 424–431CrossRefPubMedGoogle Scholar
  45. Muramatsu H, Nagai K (2013) Streptomyces tsukubensis sp. nov., a producer of the immunosuppressant tacrolimus. J Antibiot (Tokyo) 66(4):251–254CrossRefGoogle Scholar
  46. Murray JE, Sheil AGR, Moseley R, Knight P, McGavic JD, Dammin GJ (1964) Analysis of mechanism of immunosuppressive drugs in renal Homotransplantation. Ann Surg 160(3):449–473CrossRefPubMedPubMedCentralGoogle Scholar
  47. Naesens M, Kuypers DR, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4(2): 481–508PubMedGoogle Scholar
  48. Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, Marcus R, Parameshwar J, Ramsay A, Newstead C, Haemato-oncology Task Force of the British Committee for Standards in Haematology, and British Transplantation Society (2010) Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients – BCSH and BTS guidelines. Br J Haematol 149(5):675–692CrossRefPubMedGoogle Scholar
  49. Perico N, Remuzzi G (1997) Prevention of transplant rejection: current treatment guidelines and future developments. Drugs 54(4):533–570CrossRefPubMedGoogle Scholar
  50. Perico N, Dadan J, Remuzzi G (1990) Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat. J Am Soc Nephrol 1(1):76–83PubMedGoogle Scholar
  51. Reshef R, Vardhanabhuti S, Luskin MR, Heitjan DF, Hadjiliadis D, Goral S, Krok KL, Goldberg LR, Porter DL, Stadtmauer EA, Tsai DE (2011) Reduction of immunosuppression as initial therapy for posttransplantation lymphoproliferative disorder (bigstar). Am J Transplant 11(2):336–347CrossRefPubMedPubMedCentralGoogle Scholar
  52. Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S (2011) Induced immune tolerance for kidney transplantation. N Engl J Med 365(14):1359–1360CrossRefPubMedPubMedCentralGoogle Scholar
  53. Scheffert JL, Raza K (2014) Immunosuppression in lung transplantation. J Thorac Dis 6(8):1039–1053PubMedPubMedCentralGoogle Scholar
  54. Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin a and FK506. Immunol Today 13(4):136–142CrossRefPubMedGoogle Scholar
  55. Schwartz RB, Bravo SM, Klufas RA, Hsu L, Barnes PD, Robson CD, Antin JH (1995) Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. AJR Am J Roentgenol 165(3):627–631CrossRefPubMedGoogle Scholar
  56. Sikma MA, van Maarseveen EM, van de Graaf EA, Kirkels JH, Verhaar MC, Donker DW, Kesecioglu J, Meulenbelt J (2015) Pharmacokinetics and toxicity of tacrolimus early after heart and lung transplantation. Am J Transplant 15(9):2301–2313CrossRefPubMedGoogle Scholar
  57. Starzl TE (2000) History of clinical transplantation. World J Surg 24(7):759–782CrossRefPubMedPubMedCentralGoogle Scholar
  58. Starzl TE, Marchioro TL, Waddell WR (1963) The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 117:385–395PubMedPubMedCentralGoogle Scholar
  59. Strandgaard S, Paulson OB (1984) Cerebral autoregulation. Stroke 15(3):413–416CrossRefPubMedGoogle Scholar
  60. Sweet SC (2013) Induction therapy in lung transplantation. Transpl Int 26(7):696–703CrossRefPubMedGoogle Scholar
  61. Tam CS, Galanos J, Seymour JF, Pitman AG, Stark RJ, Prince HM (2004) Reversible posterior leukoencephalopathy syndrome complicating cytotoxic chemotherapy for hematologic malignancies. Am J Hematol 77(1):72–76CrossRefPubMedGoogle Scholar
  62. Treede H, Glanville AR, Klepetko W, Aboyoun C, Vettorazzi E, Lama R, Bravo C, Knoop C, Aubert JD, Reichenspurner H, European and Australian Investigators in Lung Transplantation (2012) Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation. J Heart Lung Transplant 31(8): 797–804CrossRefPubMedGoogle Scholar
  63. Vos R, Verleden SE, Ruttens D, Vandermeulen E, Yserbyt J, Dupont LJ, Van Raemdonck DE, De Raedt N, Gheysens O, De Jong PA, Verleden GM, Vanaudenaerde BM (2013) Pirfenidone: a potential new therapy for restrictive allograft syndrome? Am J Transplant 13(11):3035–3040CrossRefPubMedGoogle Scholar
  64. Witt CA, Hachem RR (2013) Immunosuppression: What’s standard and What’s new? Semin Respir Crit Care Med 34(03):405–413CrossRefPubMedGoogle Scholar
  65. Yates B, Murphy DM, Forrest IA, Ward C, Rutherford RM, Fisher AJ, Lordan JL, Dark JH, Corris PA (2005) Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 172(6):772–775CrossRefPubMedGoogle Scholar
  66. Yusen RD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb SB, Levvey BJ, Lund LH, Meiser B, Rossano JW, Stehlik J (2015) The registry of the International Society for Heart and Lung Transplantation: thirty-second official adult lung and heart-lung transplantation report – 2015; Focus theme: early graft failure. J Heart Lung Transplant 34(10): 1264–1277CrossRefPubMedGoogle Scholar
  67. Zuckermann A, Reichenspurner H, Birsan T, Treede H, Deviatko E, Reichart B, Klepetko W (2003) 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 125(4):891–900CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.St. Louis Children’s HospitalSt. LouisUSA

Section editors and affiliations

  • Samuel B Goldfarb
    • 1
  1. 1.The Children's Hospital of PhiladelphiaPhiladelphiaUSA

Personalised recommendations