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Prognostic value of cytotoxic T-lymphocytes and CD40 in biopsies with early renal allograft rejection

  • Original Article
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Transplant International

Abstract

After renal transplantation, different immunological and non-immunological factors lead to long-term allograft deterioration. Acute rejection episodes are one risk factor for chronic renal allograft dysfunction (CRAD). Following the current Banff classification the histological grade in acute rejection episodes is of limited prognostic value, therefore, additional morphological surrogate markers would be helpful. We investigated the biopsies of 91 patients with early acute rejection episodes for the immunohistochemical expression of key molecules (perforin, granzyme B, TIA-1, CD40) in the T cell-mediated rejection process. Staining results were correlated to long-term allograft outcome. Patients with greater than 2% of granzyme B or greater than 25% of CD40-positive cells in the interstitial infiltrate showed significantly shorter allograft survival. Patients with a CD40-positive vascular rejection or greater than 2% of granzyme B-positive cells in the interstitial infiltrate were significantly correlated with an earlier onset of CRAD. Our findings provide potential morphological surrogate markers in biopsies with early acute rejection episodes after renal transplantation. These could become part of combined clinical and histological algorithms, allowing patient-specific risk estimation and customized therapy options to be made.

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References

  1. Colvin RB. The renal allograft biopsy. Kidney Int 1996; 50:1069–1082.

    CAS  PubMed  Google Scholar 

  2. Nickeleit V, Vamvakas EC, Pascual M, Poletti BJ, Colvin RB. The prognostic significance of specific arterial lesions in acute renal allograft rejection. J Am Soc Nephrol 1998; 9:1301–1308.

    CAS  Google Scholar 

  3. Kreis HA and Ponticelli C. Causes of late renal allograft loss: Chronic allograft dysfunction, death, and other factors. Transplantation 2001;71 (Suppl): SS5-SS9.

    Google Scholar 

  4. Gulanikar AC, MacDonald AS, Sungurtekin U, Belitsky P. The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants. Transplantation 1992; 53:323–328.

    CAS  PubMed  Google Scholar 

  5. Almond PS, Matas AJ, Gillingham KJ, Dunn DL, Payne WD, Gores P, Gruessner R, Najarian JS. Predictors of chronic rejection in renal transplant recipients. Transplant Proc 1993; 25:936

    CAS  PubMed  Google Scholar 

  6. Basadonna GP, Matas AL, Gillingham KJ, Payne WD, Dunn DL, Sutherland DE, Gores PF, Gruessner RW, Najarian JS. Early versus late acute renal allograft rejection: impact on chronic rejection. Transplantation 1993; 55:993–995.

    CAS  PubMed  Google Scholar 

  7. Tejani A, Cortes L, Stablein D. Clinical correlates of chronic rejection in pediatric renal transplantation. A report of the North American Pediatric Renal Transplant Cooperative Study. Transplantation 1996; 61:1054–1058.

    CAS  PubMed  Google Scholar 

  8. Matas AL, Gillingham KJ, Payne WD, Najarian JS. The impact of an acute rejection episode on long-term renal allograft survival. Transplantation 1994; 57:857–859.

    CAS  PubMed  Google Scholar 

  9. Leggat JE, Ojo AO, Leichtman AB, Port FK, Wolfe RA, Turenne MN, Held PJ. Long-term renal allograft survival: prognostic implications of the timing of acute rejection episodes. Transplantation 1997; 63:1268–1272.

    PubMed  Google Scholar 

  10. Paul LC. Immunologic risk factors for chronic renal allograft dysfunction. Transplantation 2001; 71 (Suppl): SS17-SS23.

    Google Scholar 

  11. Colvin RB, Cohen A, Siaontz C, Bonsib S, Buick M, Burke B, Carter S, Cavallo T, Haas M, Lindblad A. Evaluation of the pathologic criteria for acute renal allograft rejection: Reproducibility, sensitivity and clinical correlation. J Am Soc Nephrol 1997; 8:1930–1941.

    CAS  PubMed  Google Scholar 

  12. Van Saase JL, van der Woude FJ, Thorogood J, Hollander AA, van Es LA, Weening JJ, van Bockel JH, Bruijn JA. The relation between acute vascular and interstitial renal allograft rejection and subsequent chronic rejection. Transplantation 1995; 59:1280–1285.

    PubMed  Google Scholar 

  13. Mihatsch MJ, Nickeleit V, Gudat F. Morphologic criteria of chronic renal allograft rejection. Transplant Proc 1999; 31:1295–1297.

    CAS  PubMed  Google Scholar 

  14. Meehan SM, McCluskey RT, Pascual M, Preffer FI, Anderson P, Schlossman SF, Colvin RB. Cytotoxicity and apoptosis in human renal allografts: Identification, distribution, and quantification of cells with a cytotoxic granule protein GMP-17 (TIA-1) and cells with fragmented nuclear DNA. Lab Invest 1997; 76:639–649.

    CAS  PubMed  Google Scholar 

  15. Wever PC, Boonstra JG, Laterveer JC, Hack CE, van der Woude FJ, Daha MR, Ten Berge IJM. Mechanisms of lymphocyte-mediated cytotoxicity in acute renal allograft rejection. Transplantation 1998; 66:259–264.

    Article  CAS  PubMed  Google Scholar 

  16. Olive C, Cheung C, Falk MC. Apoptosis and expression of cytotoxic T lymphocyte effector molecules in renal allografts. Transplant Immunol 1999; 7:27–36.

    Article  CAS  Google Scholar 

  17. Lipman ML, Stevens AC, Bleackley RC, Helderman JH, McCune TR, Harmon WE, Shapiro ME, Rosen S, Strom TB. The strong correlation of cytotoxic T lymphocyte-specific serine protease gene transcripts with renal allograft rejection. Transplantation 1992; 53:73–79.

    CAS  PubMed  Google Scholar 

  18. Kummer JA, Wever PC, Kamp AM, Ten Berge IJM, Hack CE, Weening JJ. Expression of Granzyme A and B proteins by cytotoxic lymphocytes involved in acute renal allograft rejection. Kidney Int 1995; 47:70–77.

    CAS  PubMed  Google Scholar 

  19. Strehlau J, Pavlakis M, Lipman M, Shapiro M, Vasconcellos L, Harmon W, Strom TB. Quantitative detection of immune activation transcripts as a diagnostic tool in kidney transplantation. Proc Nat Acad Sci 1997; 94:695–700.

    Article  CAS  PubMed  Google Scholar 

  20. Lipman ML, Shen Y, Jeffery JR, Gough J, McKenna RM, Grimm PC, Rush DN. Immune-activation gene expression in clinically stable renal allograft biopsies: molecular evidence for subclinical rejection. Transplantation 1998; 66:1673–1681.

    Article  CAS  PubMed  Google Scholar 

  21. Hong SW, Jeong HJ, Kim SI, Moon JI, Kim YS, Park K. Granzyme B and TIA-1 expression in chronic and acute on chronic renal allograft rejection. Yonsei Med J 2001; 41:285–290.

    Google Scholar 

  22. Rukavina D, Balen-Marunic S, Rubesa G, Orlic P, Vujaklija K, Podack ER. Perforin expression in peripheral blood lymphocytes in rejecting and tolerant kidney transplant recipients. Transplantation 1996; 61:285–291.

    Article  CAS  PubMed  Google Scholar 

  23. Li B, Hartono C, Ding R, Sharma VK, Ramaswamy R, Qian B, Serur D, Mouradian J, Schwarz JE, Suthanthiran M. Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. New Engl J Med 2001; 344:947–954.

    Article  CAS  PubMed  Google Scholar 

  24. Denton MD, Reul RM, Dharnidharka VR, Fang JC, Ganz P, Briscoe DM. Central role for CD 40/CD 40 ligand (CD154) interactions in transplant rejection. Pediatr Transplant 1998; 2:6-15.

    CAS  PubMed  Google Scholar 

  25. Sayegh MH and Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. New Engl J Med 1998; 338:1813–1821.

    Article  CAS  PubMed  Google Scholar 

  26. Kirk AD, Burkly LC, Batty DS, Baumgartner RE, Bering JD, Buchanan K, Fechner JH, Germond RL, Kampen RL, Patterson NB, Swanson SJ, Tadaki DM, TenHoor CN, White L, Knechtle SJ, Harlan DM. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nature Med 1999; 5:686–693.

    Article  CAS  PubMed  Google Scholar 

  27. Kunzendorf U. Co-stimulatory signals during recognition of allo-antigens. Kidney Blood Press Res 2000; 23:175–176.

    Article  CAS  PubMed  Google Scholar 

  28. Bennett SRM, Carbone FR, Karamalis F, Flavell RA, Miller JFAP, Heath WR. Help for cytotoxic-T-cells response is mediated by CD 40 signaling. Nature 1998; 393:478–480.

    CAS  PubMed  Google Scholar 

  29. Schoenberger SP, Toes REM, van der Voort EIH, Offringa R, Melief CJM. T-cell help for cytotoxic T lymphocytes is mediated by CD 40-CD 40L interactions. Nature 1998; 393:480–483.

    CAS  PubMed  Google Scholar 

  30. Biancone L, Donati D, Segoloni G, Turello E, Squiccimarro G, Bussolati B, Cantaluppi V, Amann F, Gastaldi L, Piccoli G, Camussi G. Study of Lymphocyte costimulatory molecules in renal transplantation. Transplant Proc 1998; 30:2384–2386.

    Article  CAS  PubMed  Google Scholar 

  31. Gaweco AS, Mitchell BL, Lucas BA, McClatchey KD, van Thiel DH. CD 40 expression on graft infiltrates and parenchymal CD154 (CD 40L) induction in human chronic renal allograft rejection. Kidney Int 1999; 55:1543–1552

    PubMed  Google Scholar 

  32. Masanek U, Yard BA, van der Woude FJ. Functional properties of CD 40-stimulation of proximal tubular epithelial cells. Kidney Blood Press Res 2000; 23:266 (abstract).

    Google Scholar 

  33. Kamoun M. Cellular and molecular parameters in human renal allograft rejection. Clinical Biochem 2001; 34:29–34.

    Article  CAS  Google Scholar 

  34. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, Demetris AJ, Drachenberg B, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindblad AS, Marcussen N, Mihatsch MJ, Nadasdy T, Nickerson P, Olsen TS, Papadimitriou JC, Randhawa PS, Rayner DC, Roberts I, Rose S, Rush D, Salinas-Madrigal L, Salomon DR, Sund S, Taskinen E, Trpkov K, Yamaguchi Y. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713–723.

    CAS  PubMed  Google Scholar 

  35. Racusen LC, Colvin RB, Solez K, Mihatsch MJ, Halloran PF, Campbell PM, Cecka MJ, Cosyns JP, Demetris AJ, Fishbein MC, Fogo A, Furness P, Gibson IW, Glotz D, Hayry P, Hunsickern L, Kashgarian M, Kerman R, Magil AJ, Montgomery R, Morozumi K, Nickeleit V, Randhawa P, Regele H, Seron D, Seshan S, Sund S, Trpkov K. Antibody-mediated rejection criteria—an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant. 2003 Jun;3(6):708–14.

    Google Scholar 

  36. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. New Engl J Med 2000; 342:605–612.

    Article  CAS  PubMed  Google Scholar 

  37. Furness PN, Taub N. International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project. Kidney Int. 2001; 60(5):1998–2012

    Google Scholar 

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Acknowledgements

We are grateful to Sanja Galgoci and Regina Brauner-Lottes for skilful technical assistance. We thank Helen Cathro, M.B., Ch.B. (UVA, Charlottesville, Virginia) for critical review of the manuscript and stimulating comments. M.M. received financial support from the Hochschulinterne Leistungsförderung (HiLF) as a grant from the Medizinische Hochschule Hannover, Germany

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Author notes

  1. Matthias Behrend

    Present address: Department of Surgery, Klinikum Deggendorf, Deggendorf, Germany

Authors and Affiliations

  1. Institute of Pathology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625, Hanover, Germany

    Michael Mengel, Imke Mueller, Reinhard von Wasielewski & Hans Kreipe

  2. Department of Transplant Surgery, Medizinische Hochschule Hannover, Hanover, Germany

    Matthias Behrend

  3. Department of Nephrology, Medizinische Hochschule Hannover, Hanover, Germany

    Joerg Radermacher, Anke Schwarz & Hermann Haller

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  1. Michael Mengel
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Correspondence to Michael Mengel.

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Mengel, M., Mueller, I., Behrend, M. et al. Prognostic value of cytotoxic T-lymphocytes and CD40 in biopsies with early renal allograft rejection. Transpl Int 17, 293–300 (2004). https://doi.org/10.1007/s00147-004-0691-x

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  • DOI: https://doi.org/10.1007/s00147-004-0691-x

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