Immunologische Aspekte nach der Lungentransplantation

Zusammenfassung

Die Lungentransplantation hat sich seit den 1980er-Jahren durch Fortschritte in chirurgischen Techniken und der Einführung von Immunsuppressiva wie Ciclosporin zu einem etablierten Therapieverfahren entwickelt. Trotz verbesserter kurzzeitiger Ergebnisse bleibt die Langzeitprognose, insbesondere durch immunologische Komplikationen, eingeschränkt. Mit einer medianen Überlebenszeit von etwa 6 Jahren ist die Lunge aufgrund ihrer Exposition gegenüber Umweltantigenen und einer großen vaskulären Endothelfläche das solide Organ mit der größten Immunogenität. Nach einer Lungentransplantation spielen verschiedene Formen der Alloreaktivität, einschl. der T-Zell-vermittelten akuten und chronischen Abstoßungen eine zentrale Rolle. Ergänzend tragen humorale Immunantworten durch die Bildung donorspezifischer und Non-HLA-Antikörper zur Transplantatschädigung bei. Wiederkehrende Gewebeschäden, etwa durch Ischämie-Reperfusions-Schäden, führen zur Freilegung kryptischer Antigene, fördern autoreaktive Prozesse und begünstigen die Bildung tertiärer lymphatischer Organe. Diese Prozesse unterhalten eine anhaltende Entzündungsreaktion, die zur chronischen Transplantatdysfunktion führen kann. Abstoßungsreaktionen bleiben eine große Herausforderung. Akute Formen, wie zelluläre und humorale Abstoßungen, erfordern schnelle, gezielte Therapien, um irreversible Schäden zu verhindern. Chronische Abstoßungen, insbesondere die chronische Lungenallograft-Dysfunktion (CLAD) verschlechtern die Lungenfunktion langfristig. Die Unterscheidung der Hauptphänotypen der CLAD, dem Bronchiolitis-obliterans-Syndrom und dem restriktiven Allograft-Syndrom, ist entscheidend für Prognose und Therapie. Dennoch sind die Behandlungsmöglichkeiten limitiert, sodass eine Retransplantation oft die letzte Option darstellt. Die immunsuppressive Therapie bildet die Grundlage zur Prävention von Abstoßungen. Sie umfasst meist eine Dreifachkombination aus Calcineurininhibitoren, antiproliferativen Substanzen und Kortikosteroiden. Für die Induktionstherapie kommen monoklonale oder polyklonale Antikörper zum Einsatz. Moderne Strategien zielen darauf ab, Immunantworten effektiv zu unterdrücken und gleichzeitig schwerwiegende Nebenwirkungen wie Infektionen, Malignome und Nephrotoxizität zu minimieren. Zukünftige Forschungsansätze fokussieren sich auf personalisierte Immunsuppressionsstrategien, optimierte Diagnostik und innovative Therapieansätze, um die Langzeitprognose von Lungentransplantierten zu verbessern.

Abstract

Since the 1980 s, lung transplantation has evolved into an established therapeutic procedure, due to advancements in surgical techniques and the introduction of immunosuppressants such as cyclosporine. Despite improved short-term outcomes, the long-term prognosis remains limited, primarily due to immunological complications. With a median survival of approximately six years, the lung is the most immunogenic solid organ, owing to its constant exposure to environmental antigens and its extensive vascular endothelial surface. After lung transplantation, various forms of alloreactivity, including T cell-mediated acute and chronic rejection, play a central role. Additionally, humoral immune responses, characterised by the production of donor-specific and non-HLA antibodies, contribute significantly to graft injury. Recurrent tissue damage, such as ischemia reperfusion injury, leads to the exposure of cryptic antigens, promotes autoreactive processes, and facilitates the formation of tertiary lymphoid organs. These mechanisms sustain persistent inflammation, ultimately resulting in chronic graft dysfunction. Rejection reactions remain a major challenge. Acute forms, such as cellular and humoral rejection, require rapid and targeted therapies to prevent irreversible damage. Chronic rejection, particularly chronic lung allograft dysfunction (CLAD), progressively impairs lung function. In the main phenotypes of CLAD, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are crucial for prognosis and treatment. Nevertheless, therapeutic options remain limited, and retransplantation is often the last resort. Immunosuppressive therapy forms the cornerstone of rejection prevention, and typically employs a triple combination of calcineurin inhibitors, antiproliferative agents, and corticosteroids. Induction therapy frequently involves monoclonal or polyclonal antibodies. Modern strategies aim to effectively suppress immune responses while minimising severe side effects, such as infections, malignancies, and nephrotoxicity. Future research will focus on personalised immunosuppressive strategies, optimised diagnostics, and innovative therapies to improve the long-term prognosis of lung transplant recipients.

Schlüsselwörter

Transplantation - Lunge - Immunsuppression

Keywords

transplantation - lung - immune suppression

Publication History

Received: 19 January 2025

Accepted: 02 April 2025

Article published online:
13 May 2025

• Literatur

• 1 Hardy JD, Webb WR, Dalton ML. et al. Lung Homotransplantation in Man. JAMA 1963; 186: 1065-1074
• 2 Fernando ON, Sweny P, Farrington K. et al. Preliminary experience with cyclosporin A in human renal allografts. Transplant Proc 1980; 12: 244-245
• 3 Chambers DC, Cherikh WS, Harhay MO. et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart–lung transplantation Report—2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant 2019; 38: 1042-1055
• 4 Aw MM. Transplant immunology. J Pediatr Surg 2003; 38: 1275-1280
• 5 Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cell alloreactivity during allograft rejection in mice. J Immunol 1999; 162: 352-358
• 6 Lechler RI, Batchelor JR. Immunogenicity of retransplanted rat kidney allografts. Effect of inducing chimerism in the first recipient and quantitative studies on immunosuppression of the second recipient. J Exp Med 1982; 156: 1835-1841
• 7 Benichou G, Takizawa PA, Ho PT. et al. Immunogenicity and tolerogenicity of self-major histocompatibility complex peptides. J Exp Med 1990; 172: 1341-1346
• 8 Benichou G, Fedoseyeva E, Lehmann PV. et al. Limited T cell response to donor MHC peptides during allograft rejection. Implications for selective immune therapy in transplantation. J Immunol 1994; 153: 938-945
• 9 Boisgérault F, Anosova NG, Tam RC. et al. Induction of T-cell response to cryptic MHC determinants during allograft rejection. Hum Immunol 2000; 61: 1352-1362
• 10 Suciu-Foca N, Harris PE, Cortesini R. Intramolecular and intermolecular spreading during the course of organ allograft rejection. Immunol Rev 1998; 164: 241-246
• 11 Marino J, Paster J, Benichou G. Allorecognition by T Lymphocytes and Allograft Rejection. Front Immunol 2016; 7: 582
• 12 Joly E, Hudrisier D. What is trogocytosis and what is its purpose?. Nat Immunol 2003; 4: 815
• 13 Knight SC, Iqball S, Roberts MS. et al. Transfer of antigen between dendritic cells in the stimulation of primary T cell proliferation. Eur J Immunol 1998; 28: 1636-1644
• 14 Brown K, Sacks SH, Wong W. Extensive and bidirectional transfer of major histocompatibility complex class II molecules between donor and recipient cells in vivo following solid organ transplantation. FASEB J 2008; 22: 3776-3784
• 15 Marino J, Babiker-Mohamed MH, Crosby-Bertorini P. et al. Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Sci Immunol 2016; 1: aaf8759
• 16 Cyster JG, Allen CDC. B Cell Responses: Cell Interaction Dynamics and Decisions. Cell 2019; 177: 524-540
• 17 McHeyzer-Williams M, Okitsu S, Wang N. et al. Molecular programming of B cell memory. Nat Rev Immunol 2011; 12: 24-34
• 18 Li Y, Ma L, Yin D. et al. Long-term control of alloreactive B cell responses by the suppression of T cell help. J Immunol 2008; 180: 6077-6084
• 19 Rabant M, Gorbacheva V, Fan R. et al. CD40-independent help by memory CD4 T cells induces pathogenic alloantibody but does not lead to long-lasting humoral immunity. Am J Transplant 2013; 13: 2831-2841
• 20 Burns AM, Chong AS. Alloantibodies prevent the induction of transplantation tolerance by enhancing alloreactive T cell priming. J Immunol 2011; 186: 214-221
• 21 Bordron A, Révélen R, D’Arbonneau F. et al. Functional heterogeneity of anti-endothelial cell antibodies. Clin Exp Immunol 2001; 124: 492-501
• 22 Zou Y, Stastny P, Süsal C. et al. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 2007; 357: 1293-1300
• 23 Brasile L, Rodman E, Shield CF. et al. The association of antivascular endothelial cell antibody with hyperacute rejection: a case report. Surgery 1986; 99: 637-640
• 24 Reinsmoen NL, Lai CH, Heidecke H. et al. Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients. Transplantation 2010; 90: 1473-1477
• 25 Dragun D, Müller DN, Bräsen JH. et al. Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 2005; 352: 558-569
• 26 Fuss A, Hope CM, Deayton S. et al. C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies. Nephrology (Carlton) 2015; 20: 467-473
• 27 Burlingham WJ, Love RB, Jankowska-Gan E. et al. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest 2007; 117: 3498-3506
• 28 Hachem RR, Tiriveedhi V, Patterson GA. et al. Antibodies to K-α 1 tubulin and collagen V are associated with chronic rejection after lung transplantation. Am J Transplant 2012; 12: 2164-2171
• 29 Tiriveedhi V, Angaswamy N, Brand D. et al. A shift in the collagen V antigenic epitope leads to T helper phenotype switch and immune response to self-antigen leading to chronic lung allograft rejection. Clin Exp Immunol 2012; 167: 158-168
• 30 Yoshida S, Haque A, Mizobuchi T. et al. Anti-type V collagen lymphocytes that express IL-17 and IL-23 induce rejection pathology in fresh and well-healed lung transplants. Am J Transplant 2006; 6: 724-735
• 31 Zhang Q, Reed EF. The importance of non-HLA antibodies in transplantation. Nat Rev Nephrol 2016; 12: 484-495
• 32 Cardinal H, Dieudé M, Brassard N. et al. Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury. Am J Transplant 2013; 13: 861-874
• 33 Carroll MC. The complement system in regulation of adaptive immunity. Nat Immunol 2004; 5: 981-986
• 34 Dempsey PW, Allison ME, Akkaraju S. et al. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 1996; 271: 348-350
• 35 Reed EF, Tugulea SL, Suciu-Foca N. Influence of HLA class I and class II antigens on the peripheral T-cell receptor repertoire. Hum Immunol 1994; 40: 111-122
• 36 Valujskikh A, Lantz O, Celli S. et al. Cross-primed CD8(+) T cells mediate graft rejection via a distinct effector pathway. Nat Immunol 2002; 3: 844-851
• 37 Macdonald WA, Chen Z, Gras S. et al. T cell allorecognition via molecular mimicry. Immunity 2009; 31: 897-908
• 38 Sumpter TL, Wilkes DS. Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection. Am J Physiol Lung Cell Mol Physiol 2004; 286: L1129-L1139
• 39 Fan L, Benson HL, Vittal R. et al. Neutralizing IL-17 prevents obliterative bronchiolitis in murine orthotopic lung transplantation. Am J Transplant 2011; 11: 911-922
• 40 Braun RK, Molitor-Dart M, Wigfield C. et al. Transfer of tolerance to collagen type V suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection. Transplantation 2009; 88: 1341-1348
• 41 Gorbacheva V, Fan R, Li X. et al. Interleukin-17 promotes early allograft inflammation. Am J Pathol 2010; 177: 1265-1273
• 42 Vanaudenaerde BM, De Vleeschauwer SI, Vos R. et al. The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation. Am J Transplant 2008; 8: 1911-1920
• 43 Murphy DM, Forrest IA, Corris PA. 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
• 44 Hsu HC, Yang P, Wang J. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008; 9: 166-175
• 45 Sato M, Hirayama S, Hwang DM. et al. The role of intrapulmonary de novo lymphoid tissue in obliterative bronchiolitis after lung transplantation. J Immunol 2009; 182: 7307-7316
• 46 Patakas A, Benson RA, Withers DR. et al. Th17 effector cells support B cell responses outside of germinal centres. PLoS One 2012; 7: e49715
• 47 Rangel-Moreno J, Carragher DM, de la Luz Garcia-Hernandez M. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol 2011; 12: 639-646
• 48 Szodoray P, Jellestad S, Teague MO. et al. Attenuated apoptosis of B cell activating factor-expressing cells in primary Sjögren’s syndrome. Lab Invest 2003; 83: 357-365
• 49 Miller CL, Allan JS. O JM. et al. Novel approaches for long-term lung transplant survival. Front Immunol 2022; 13: 931251
• 50 Masson E, Stern M, Chabod J. et al. Hyperacute rejection after lung transplantation caused by undetected low-titer anti-HLA antibodies. J Heart Lung Transplant 2007; 26: 642-645
• 51 Frost AE, Jammal CT, Cagle PT. Hyperacute rejection following lung transplantation. Chest 1996; 110: 559-562
• 52 Martinu T, Pavlisko EN, Chen DF. et al. Acute allograft rejection: cellular and humoral processes. Clin Chest Med 2011; 32: 295-310
• 53 Diamond JM, Lee JC, Kawut SM. et al. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med 2013; 187: 527-534
• 54 Lee JC, Christie JD. Primary graft dysfunction. Clin Chest Med 2011; 32: 279-293
• 55 Suzuki Y, Cantu E, Christie JD. Primary graft dysfunction. Semin Respir Crit Care Med 2013; 34: 305-319
• 56 Saris SC, Wright DC, Oldfield EH. et al. Intravascular streaming and variable delivery to brain following carotid artery infusions in the Sprague-Dawley rat. J Cereb Blood Flow Metab 1988; 8: 116-120
• 57 Van Raemdonck D, Hartwig MG, Hertz MI. et al. Report of the ISHLT Working Group on primary lung graft dysfunction Part IV: Prevention and treatment: A 2016 Consensus Group statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2017; 36: 1121-1136
• 58 Jaksch P, Hoetzenecker K. Lungentransplantation. Pneumologe (Berl) 2020; 17: 285-296
• 59 Stewart S, Fishbein MC, Snell GI. et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant 2007; 26: 1229-1242
• 60 Rudzik KN, Moore CA, Sacha LM. et al. Rabbit Antithymocyte Globulin for Treatment of Corticosteroid Refractory Acute Cellular Rejection After Lung Transplantation. Transplantation 2023; 107: 1828-1834
• 61 Bery AI, Hachem RR. Antibody-mediated rejection after lung transplantation. Ann Transl Med 2020; 8: 411
• 62 Levine DJ, Glanville AR, Aboyoun C. et al. Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2016; 35: 397-406
• 63 Glanville AR. Antibody-mediated rejection in lung transplantation: myth or reality?. J Heart Lung Transplant 2010; 29: 395-400
• 64 Verleden GM, Glanville AR, Lease ED. et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant 2019; 38: 493-503
• 65 Nykänen A, Raivio P, Peräkylä L. et al. Incidence and impact of chronic lung allograft dysfunction after lung transplantation – single-center 14-year experience. Scand Cardiovasc J 2020; 54: 192-199
• 66 Bos S, Milross L, Filby AJ. et al. Immune processes in the pathogenesis of chronic lung allograft dysfunction: identifying the missing pieces of the puzzle. Eur Respir Rev 2022; 31: 220060
• 67 Bos S, Filby AJ, Vos R. et al. Effector immune cells in chronic lung allograft dysfunction: A systematic review. Immunology 2022; 166: 17-37
• 68 Blumenstock DA, Lewis C. The first transplantation of the lung in a human revisited. Ann Thorac Surg 1993; 56: 1423-1424
• 69 Nelson J, Alvey N, Bowman L. et al. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and International Society for Heart and Lung Transplantation: An executive summary. Pharmacotherapy 2022; 42: 594-598
• 70 Small B, Au J, Brink H. et al. Induction and maintenance immunosuppression in lung transplantation. Indian J Thorac Cardiovasc Surg 2022; 38: 300-317
• 71 Scheffert JL, Raza K. Immunosuppression in lung transplantation. J Thorac Dis 2014; 6: 1039-1053
• 72 Small B, Au J, Brink H. et al. Induction and maintenance immunosuppression in lung transplantation. Indian J Thorac Cardiovasc Surg 2022; 38: 300-317
• 73 Atkinson BJ, Sharma NS. Immunosuppression in lung transplantation: a narrative review. Curr Chall Thorac Surg 2023; 5: 21
• 74 Bamgbola FO, Del Rio M, Kaskel FJ. et al. Non-cardiogenic pulmonary edema during basiliximab induction in three adolescent renal transplant patients. Pediatr Transplant 2003; 7: 315-320
• 75 Millennium and ILEX Partners, LP. Package Insert Campath® (ALEMTUZUMAB). Cambridge, MA 2003 Accessed April 27, 2025 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/alemmil050701LB.htm
• 76 Benazzo A, Schwarz S, Muckenhuber M. et al. Alemtuzumab induction combined with reduced maintenance immunosuppression is associated with improved outcomes after lung transplantation: A single centre experience. PLoS One 2019; 14: e0210443
• 77 Benazzo A, Auner S, Boehm PM. et al. Outcomes with alemtuzumab induction therapy in lung transplantation: a comprehensive large-scale single-center analysis. Transpl Int 2021; 34: 2633-2643
• 78 Hartwig MG, Snyder LD, Appel JZ. et al. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation. J Heart Lung Transplant 2008; 27: 547-553
• 79 Mullen JC, Oreopoulos A, Lien DC. et al. A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation. J Heart Lung Transplant 2007; 26: 504-510
• 80 Taylor AL, Watson CJE, Bradley JA. Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005; 56: 23-46
• 81 Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology 2000; 47: 119-125
• 82 Novartis Pharmaceuticals Corporation. Sandimmune [Package Insert]. East Hanover, NJ 2006 Accessed April 27, 2025 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050573s039,050574s047,050625s053lbl.pdf
• 83 Astellas Pharma Inc. Prograf® [Package Insert]. Deerfield, IL 2012 Accessed April 27, 2025 at: https://www.astellas.com/us/system/files/prograf_7.pdf
• 84 Christie JD, Edwards LB, Kucheryavaya AY. et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012; 31: 1073-1086
• 85 Prometheus Laboratories Inc. Imuran® [Package Insert]. San Diego, CA 2011 Accessed April 27, 2025 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf
• 86 Roche Laboratories Inc. CellCept® [Package Insert]. Nutley, NJ 1998 Accessed April 27, 2025 at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050722s021,050723s019,050758s019,050759s024lbl.pdf
• 87 Speich R, Schneider S, Hofer M. et al. Mycophenolate mofetil reduces alveolar inflammation, acute rejection and graft loss due to bronchiolitis obliterans syndrome after lung transplantation. Pulm Pharmacol Ther 2010; 23: 445-449
• 88 McNeil K, Glanville AR, 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
• 89 Whyte RI, Rossi SJ, Mulligan MS. et al. Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation. Ann Thorac Surg 1997; 64: 945-948
• 90 Azzola A, Havryk A, Chhajed P. et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation 2004; 77: 275-280