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Entwicklungen der Immunmodulation nach Transplantation im Hinblick auf De-novo-Malignome und Tumorrezidive

Development of immunomodulation after transplantation with respect to de novo malignancies and recurrent tumors

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Der Onkologe Aims and scope

Zusammenfassung

Hintergrund

Organtransplantierte Patienten haben ein erhöhtes Risiko, maligne Tumoren zu entwickeln. Im langfristigen Verlauf nach Organtransplantation stellen maligne Tumoren nach den kardiovaskulären Erkrankungen die zweithäufigste Todesurasche dar. Ziel dieses Reviews ist eine überblickende Darstellung der Zusammenhänge zwischen Immunmodulation und Tumorentstehung nach Organtransplantation.

Ergebnisse und Schlussfolgerung

Neben individuellen Risikofaktoren werden die immunologischen Veränderungen nach Organtransplantation als Ursache des erhöhten Krebsrisikos angesehen. Histokompatibilität, HLA-Status, die kumulative Immunsuppressionsdosis in der Induktions-, Erhaltungs- und Abstoßungsbehandlung, das mit spezifischen Immunsuppressiva assoziierte Malignitätsrisiko sowie eine erhöhte Inzidenz onkogener viraler Infektionen scheinen zum erhöhten Krebsrisiko nach Organtransplantation beizutragen. Ein gründliches Tumorscreening vor und nach Transplantation, antivirale Prophylaxen und eine so niedrig wie möglich dosierte Immunsuppression sind gegenwärtige Strategien, um das Risiko für die Entstehung maligner Tumore nach Transplantation zu senken. Die Entwicklung neuer Immunsuppressiva und Protokolle zur Toleranzinduktion und klinische Erfahrungen mit systemischen und lokalen immunbasierten Tumortherapien können zukünftig ebenso dazu beitragen wie ein besseres Verständnis der Pathomechanismen der Kanzerogenese unter Immunsuppression.

Abstract

Background

Organ transplant patients are at an increased risk to develop de novo or recurrent malignancies. In the long-term course after organ transplantation, malignancies are the second most frequent cause of mortality after cardiovascular diseases. The aim of this review is to summarize and highlight aspects of the development of malignancies in the context of immunomodulation after organ transplantation.

Results and Conclusion

In addition to individual risk factors, the immunological changes after organ transplantation are considered to be the cause for the increased incidence of malignant diseases. Histocompatibility, HLA status, the cumulative dosage of immunosuppressants for induction, maintenance and rejection therapy, the cancer risks associated with specific immunosuppressants as well as an increased incidence of oncogenic viral infections, all seem to contribute to the overall increased cancer risk of organ transplant patients. Thorough pretransplantation and posttransplantation cancer screening, antiviral prophylaxis and the lowest possible level of immunosuppression while still avoiding rejection are currently available strategies to prevent cancer in organ transplant patients. Research into new immunosuppressive drugs and induction of tolerance, systemic and local immune-based tumor therapies are potential future strategies as well as basic research to have a better understanding of the pathomechanisms of cancerogenesis under immunosuppression.

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Literatur

  1. Engels EA, Pfeiffer RM, Fraumeni JF Jr., Kasiske BL, Israni AK, Snyder JJ et al (2011) Spectrum of cancer risk among US solid organ transplant recipients. JAMA 306(17):1891–1901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vajdic CM, Leeuwen MT van (2009) Cancer incidence and risk factors after solid organ transplantation. Int J Cancer 125(8):1747–1754

    Article  CAS  PubMed  Google Scholar 

  3. Lodhi SA, Lamb KE, Meier-Kriesche HU (2011) Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success. Am J Transplant 11(6):1226–1235

    Article  CAS  PubMed  Google Scholar 

  4. Bakker NA, Imhoff GW van, Verschuuren EA, Son WJ van, Heide JJ van der, Lems SP et al (2005) HLA antigens and post renal transplant lymphoproliferative disease: HLA-B matching is critical. Transplantation 80(5):595–599

    Article  CAS  PubMed  Google Scholar 

  5. Opelz G, Dohler B (2010) Impact of HLA mismatching on incidence of posttransplant non-hodgkin lymphoma after kidney transplantation. Transplantation 89(5):567–572

    Article  CAS  PubMed  Google Scholar 

  6. Hussain SK, Makgoeng SB, Everly MJ, Goodman MT, Martinez-Maza O, Morton LM et al (2015) HLA and risk of diffuse large B‑cell Lymphoma after solid organ transplantation. Transplantation doi:http://dx.doi.org/10.1097/tp.0000000000001025

    Google Scholar 

  7. Opelz G, Dohler B (2013) Ceppellini Lecture 2012: collateral damage from HLA mismatching in kidney transplantation. Tissue Antigens 82(4):235–242

    Article  CAS  PubMed  Google Scholar 

  8. Reshef R, Luskin MR, Kamoun M, Vardhanabhuti S, Tomaszewski JE, Stadtmauer EA et al (2011) Association of HLA polymorphisms with post-transplant lymphoproliferative disorder in solid-organ transplant recipients. Am J Transplant 11(4):817–825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Montgomery JR, Berger JC, Warren DS, James NT, Montgomery RA, Segev DL (2012) Outcomes of ABO-incompatible kidney transplantation in the United States. Transplantation 93(6):603–609

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tanabe K (2007) Japanese experience of ABO-incompatible living kidney transplantation. Transplantation 84(12 Suppl):4–7

    Article  Google Scholar 

  11. Yamamoto T, Kawaguchi T, Watarai Y, Tujita M, Hiramitsu T, Nanmoku K et al (2012) Potent immunosuppression for ABO-incompatible renal transplantation may not be a risk factor for malignancy. Transplant Proc 44(1):210–213

    Article  CAS  PubMed  Google Scholar 

  12. Hall EC, Engels EA, Montgomery RA, Segev DL (2013) Cancer risk after ABO-incompatible living-donor kidney transplantation. Transplantation 96(5):476–479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Grulich AE, Leeuwen MT van, Falster MO, Vajdic CM (2007) Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370(9581):59–67

    Article  PubMed  Google Scholar 

  14. Diehl VHP, Harris N (2001) Immunosuppression related malignancies. In: DeVita VTHS, Rosenberg SA (Hrsg) Principles and practice of oncology. Lippincott Williams & Wilkins, Philadelphia, S 2339

    Google Scholar 

  15. Buell JF, Gross TG, Woodle ES (2005) Malignancy after transplantation. Transplantation 80(2 Suppl):254–264

    Article  Google Scholar 

  16. Safaeian M, Robbins HA, Berndt SI, Lynch CF, Fraumeni JF Jr., Engels EA (2016) Risk of Colorectal cancer after solid organ transplantation in the united states. Am J Transplant doi: 10.1111/ajt.13549

    PubMed  Google Scholar 

  17. Patton DF, Wilkowski CW, Hanson CA, Shapiro R, Gajl-Peczalska KJ, Filipovich AH et al (1990) Epstein-Barr virus – determined clonality in posttransplant lymphoproliferative disease. Transplantation 49(6):1080–1084

    Article  CAS  PubMed  Google Scholar 

  18. Libertiny G, Watson CJ, Gray DW, Welsh KI, Morris PJ (2001) Rising incidence of post-transplant lymphoproliferative disease in kidney transplant recipients. Br J Surg 88(10):1330–1334

    Article  CAS  PubMed  Google Scholar 

  19. Opelz G, Dohler B (2004) Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 4(2):222–230

    Article  PubMed  Google Scholar 

  20. Ganschow R, Schulz T, Meyer T, Broering DC, Burdelski M (2004) Low-dose immunosuppression reduces the incidence of post-transplant lymphoproliferative disease in pediatric liver graft recipients. J Pediatr Gastroenterol Nutr 38(2):198–203

    Article  CAS  PubMed  Google Scholar 

  21. Zwald FO, Brown M (2011) Skin cancer in solid organ transplant recipients: advances in therapy and management: part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 65(2):263–279 (quiz 80)

    Article  PubMed  Google Scholar 

  22. Penn I, First MR (1999) Merkel’s cell carcinoma in organ recipients: report of 41 cases. Transplantation 68(11):1717–1721

    Article  CAS  PubMed  Google Scholar 

  23. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS (2000) Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol 143(3):513–519

    CAS  PubMed  Google Scholar 

  24. Euvrard S, Kanitakis J, Claudy A (2003) Skin cancers after organ transplantation. N Engl J Med 348(17):1681–1691

    Article  PubMed  Google Scholar 

  25. Glover MT, Deeks JJ, Raftery MJ, Cunningham J, Leigh IM (1997) Immunosuppression and risk of non-melanoma skin cancer in renal transplant recipients. Lancet 349(9049):398

    Article  CAS  PubMed  Google Scholar 

  26. Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B et al (1998) Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 351(9103):623–628

    Article  CAS  PubMed  Google Scholar 

  27. Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I et al (2012) Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 367(4):329–339

    Article  CAS  PubMed  Google Scholar 

  28. Yarosh DB, Pena AV, Nay SL, Canning MT, Brown DA (2005) Calcineurin inhibitors decrease DNA repair and apoptosis in human keratinocytes following ultraviolet B irradiation. J Invest Dermatol 125(5):1020–1025

    Article  CAS  PubMed  Google Scholar 

  29. Ulrich C, Bichel J, Euvrard S, Guidi B, Proby CM, Kerkhof PC van de et al (2007) Topical immunomodulation under systemic immunosuppression: results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5 % cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 157(Suppl 2):25–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Penn I (1990) Cancers complicating organ transplantation. N Engl J Med 323(25):1767–1769

    Article  CAS  PubMed  Google Scholar 

  31. Hagness M, Foss A, Line PD, Scholz T, Jorgensen PF, Fosby B et al (2013) Liver transplantation for nonresectable liver metastases from colorectal cancer. Ann Surg 257(5):800–806

    Article  PubMed  Google Scholar 

  32. Schmeding M, Neumann UP (2015) Liver transplant for cholangiocarcinoma: a comeback? Exp Clin Transplant 13(4):301–308

    PubMed  Google Scholar 

  33. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M et al (1999) Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 397(6719):530–534

    Article  CAS  PubMed  Google Scholar 

  34. Koehl GE, Andrassy J, Guba M, Richter S, Kroemer A, Scherer MN et al (2004) Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 77(9):1319–1326

    Article  CAS  PubMed  Google Scholar 

  35. Lee JY, Kim YH, Yi NJ, Kim HS, Lee HS, Lee BK et al (2014) Impact of immunosuppressant therapy on early recurrence of hepatocellular carcinoma after liver transplantation. Clin Mol Hepatol 20(2):192–203

    Article  PubMed  PubMed Central  Google Scholar 

  36. Geissler EK, Schnitzbauer AA, Zulke C, Lamby PE, Proneth A, Duvoux C et al (2016) Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open-label phase 3 trial. Transplantation 100(1):116–125

    Article  CAS  PubMed  Google Scholar 

  37. Aerts M, Benteyn D, Van Vlierberghe H, Thielemans K, Reynaert H (2016) Current status and perspectives of immune-based therapies for hepatocellular carcinoma. World J Gastroenterol 22(1):253–261

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hiroishi K, Eguchi J, Baba T, Shimazaki T, Ishii S, Hiraide A et al (2010) Strong CD8(+) T‑cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol 45(4):451–458

    Article  CAS  PubMed  Google Scholar 

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Correspondence to J. Mittler.

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J. Mittler und H. Lang geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Mittler, J., Lang, H. Entwicklungen der Immunmodulation nach Transplantation im Hinblick auf De-novo-Malignome und Tumorrezidive. Onkologe 22, 461–468 (2016). https://doi.org/10.1007/s00761-016-0051-3

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