Abstract
Background
Good outcomes after renal transplantation are dependent on effective immunosuppression while minimizing infection. Alemtuzumab (Campath or Campath-1H) is an anti-CD52 humanized monoclonal IgG1 antibody which induces rapid and sustained depletion of circulating lymphocytes and has been effectively used as an immunosuppressant in post-transplant induction therapy.
Methods
We used the ImmuKnow assay to compare cell-mediated immune function in renal transplant patients treated with alemtuzumab or with conventional immunosuppressive tri-therapy. The ImmuKnow method determines the levels of adenosine triphosphate (ATP) released from CD4 cells following stimulation with a mitogen.
Results
We showed a statistically significant difference in the distribution of outcome after transplantation between the conventional and the Campath groups (P = 0.010). A significantly higher number of patients treated with alemtuzumab induction therapy were stable after transplantation compared to those treated with conventional immunosuppressive tri-therapy (96.6 vs. 75.7 %). ATP values were significantly higher in the conventional group compared to the Campath group at 180 days after transplantation (P < 0.001). ATP levels did not change significantly over time in clinically stable kidney recipients treated with alemtuzumab induction therapy (P = 0.554).
Conclusions
The ImmuKnow assay is a useful tool for evaluating the global immune response in alemtuzumab-treated renal transplant patients. Alemtuzumab-depleting induction therapy remains effective for at least 180 days.
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References
Keller MR, Burlingham WJ. Loss of tolerance to self after transplant. Semin Immunopathol. 2011;33(2):105–10. doi:10.1007/s00281-011-0252-1.
Puttarajappa C, Shapiro R, Tan HP. Antibody-mediated rejection in kidney transplantation: a review. J Transplant. 2012;2012:193724. doi:10.1155/2012/193724.
Steiner RW, Awdishu L. Steroids in kidney transplant patients. Semin Immunopathol. 2011;33(2):157–67. doi:10.1007/s00281-011-0259-7.
Gabardi S, Martin ST, Roberts KL, Grafals M. Induction immunosuppressive therapies in renal transplantation. Am J Health Syst Pharm. 2011;68(3):211–8. doi:10.2146/ajhp090636.
van den Hoogen MW, Hilbrands LB. Use of monoclonal antibodies in renal transplantation. Immunotherapy. 2011;3(7):871–80. doi:10.2217/imt.11.72.
Mahmud N, Klipa D, Ahsan N. Antibody immunosuppressive therapy in solid-organ transplant: part I. MAbs. 2010;2(2):148–56.
Tiede I, Fritz G, Strand S, Poppe D, Dvorsky R, Strand D, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003;111(8):1133–45. doi:10.1172/JCI16432.
Almawi WY, Melemedjian OK, Rieder MJ. An alternate mechanism of glucocorticoid anti-proliferative effect: promotion of a Th2 cytokine-secreting profile. Clin Transplant. 1999;13(5):365–74.
Barnes PJ. Corticosteroids: the drugs to beat. Eur J Pharmacol. 2006;533(1–3):2–14. doi:10.1016/j.ejphar.2005.12.052.
Brazelton TR, Morris RE. Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol. 1996;8(5):710–20.
Hale G, Waldmann H. From laboratory to clinic: the story of CAM PA TH-1. Methods Mol Med. 2000;40:243–66. doi:10.1385/1-59259-076-4:243.
Sureshkumar KK, Hussain SM, Zimmer BW, Marcus RJ. Emerging role of alemtuzumab in renal and renal-pancreas transplantation. Expert Opin Biol Ther. 2008;8(10):1605–25. doi:10.1517/14712598.8.10.1605.
Rebello P, Cwynarski K, Varughese M, Eades A, Apperley JF, Hale G. Pharmacokinetics of CAMPATH-1H in BMT patients. Cytotherapy. 2001;3(4):261–7. doi:10.1080/146532401317070899.
Lu TM, Yang SL, Wu WZ, Tan JM. Alemtuzumab induction therapy in highly sensitized kidney transplant recipients. Chin Med J (Engl). 2011;124(5):664–8.
Vathsala A, Ona ET, Tan SY, Suresh S, Lou HX, Casasola CB, et al. Randomized trial of alemtuzumab for prevention of graft rejection and preservation of renal function after kidney transplantation. Transplantation 2005;80(6):765–74. pii: 00007890-200509270-00009.
Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909–19. doi:10.1056/NEJMoa1009546.
Shapiro R, Basu A, Tan H, Gray E, Kahn A, Randhawa P, et al. Kidney transplantation under minimal immunosuppression after pretransplant lymphoid depletion with thymoglobulin or Campath. J Am Coll Surg. 2005;200(4):505–15 (quiz A59–61). doi:10.1016/j.jamcollsurg.2004.12.024.
Malek SK, Obmann MA, Gotoff RA, Foltzer MA, Hartle JE, Potdar S. Campath-1H induction and the incidence of infectious complications in adult renal transplantation. Transplantation 2006;81(1):17–20. pii: 00007890-200601150-00005.
Thai NL, Blisard D, Tom K, Basu A, Smetanka C, Tan H, et al. Pancreas transplantation under alemtuzumab (Campath-1H) and tacrolimus: correlation between low T-cell responses and infection. Transplantation. 2006;82(12):1649–52. doi:10.1097/01.tp.0000250655.14026.5c.
Tzakis AG, Kato T, Nishida S, Levi DM, Madariaga JR, Nery JR, et al. Preliminary experience with campath 1H (C1H) in intestinal and liver transplantation. Transplantation. 2003;75(8):1227–31. doi:10.1097/01.TP.0000065192.53065.50.
Cabrera R, Ararat M, Soldevila-Pico C, Dixon L, Pan JJ, Firpi R, et al. Using an immune functional assay to differentiate acute cellular rejection from recurrent hepatitis C in liver transplant patients. Liver Transplant. 2009;15(2):216–22. doi:10.1002/lt.21666.
Pham PT, Lipshutz GS, Kawahji J, Singer JS, Pham PC. The evolving role of alemtuzumab (Campath-1H) in renal transplantation. Drug Des Dev Ther. 2009;3:41–9.
De Serres SA, Sayegh MH, Najafian N. Immunosuppressive drugs and Tregs: a critical evaluation! Clin J Am Soc Nephrol. 2009;4(10):1661–9. doi:10.2215/CJN.03180509.
Zhou H, Wu Z, Ma L, Wu W, Yang S, Wang Q, et al. Assessing immunologic function through CD4 T-lymphocyte adenosine triphosphate levels by ImmuKnow assay in Chinese patients following renal transplantation. Transplant Proc. 2011;43(7):2574–8. doi:10.1016/j.transproceed.2011.04.012.
Sottong PR, Rosebrock JA, Britz JA, Kramer TR. Measurement of T-lymphocyte responses in whole-blood cultures using newly synthesized DNA and ATP. Clin Diagn Lab Immunol. 2000;7(2):307–11.
Kowalski R, Post D, Schneider MC, Britz J, Thomas J, Deierhoi M, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant. 2003;17(2):77–88.
Xue F, Zhang J, Han L, Li Q, Xu N, Zhou T, et al. Immune cell functional assay in monitoring of adult liver transplantation recipients with infection. Transplantation. 2010;89(5):620–6. doi:10.1097/TP.0b013e3181c690fa.
Schulick RD, Weir MB, Miller MW, Cohen DJ, Bermas BL, Shearer GM. Longitudinal study of in vitro CD4+ T helper cell function in recently transplanted renal allograft patients undergoing tapering of their immunosuppressive drugs. Transplantation. 1993;56(3):590–6.
Buttgereit F, Burmester GR, Brand MD. Bioenergetics of immune functions: fundamental and therapeutic aspects. Immunol Today. 2000;21(4):192–9. pii: S0167569900015930.
Berglund D, Bengtsson M, Biglarnia A, Berglund E, Yamamoto S, von Zur-Muhlen B, et al. Screening of mortality in transplant patients using an assay for immune function. Transpl Immunol. 2011;24(4):246–50. doi:10.1016/j.trim.2010.12.005.
Torio A, Fernandez EJ, Montes-Ares O, Guerra RM, Perez MA, Checa MD. Lack of association of immune cell function test with rejection in kidney transplantation. Transplant Proc. 2011;43(6):2168–70. doi:10.1016/j.transproceed.2011.06.056.
De Paolis P, Favaro A, Piola A, Martini F, Cristiana G, Agrati C, et al. “Immuknow” to measurement of cell-mediated immunity in renal transplant recipients undergoing short-term evaluation. Transplant Proc. 2011;43(4):1013–6. doi:10.1016/j.transproceed.2011.02.043.
Kowalski RJ, Post DR, Mannon RB, Sebastian A, Wright HI, Sigle G, et al. Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay. Transplantation. 2006;82(5):663–8. doi:10.1097/01.tp.0000234837.02126.70.
Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, et al. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation—efficacy and safety at five years. Am J Transplant. 2005;5(6):1347–53. doi:10.1111/j.1600-6143.2005.00822.x.
Morales J, Bono MR, Fierro A, Iniguez R, Zehnder C, Rosemblatt M, et al. Alemtuzumab induction in kidney transplantation: clinical results and impact on T-regulatory cells. Transplant Proc. 2008;40(9):3223–8. doi:10.1016/j.transproceed.2008.03.066.
Acknowledgments
The authors wish to thank Jianming Tan, Weizhen Wu, Shunliang Yang, Jinquan Cai, Junqi Guo, Kai Zheng, Zhixian Wu, Xia Gao, Xiaowen Chen, Qinghua Wang, Lianghu Huang, Lin Wu and Xinxiang Yuan for kind assistance. Grants received from Organ transplantation research projects of China MOH (No. IHECC07-201010), and Fujian Provincial Natural Science Foundation of China (No. 2011J01239).
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H. Zhou, J. Lin and S. Chen contributed equally to this work.
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Zhou, H., Lin, J., Chen, S. et al. Use of the ImmuKnow assay to evaluate the effect of alemtuzumab-depleting induction therapy on cell-mediated immune function after renal transplantation. Clin Exp Nephrol 17, 304–309 (2013). https://doi.org/10.1007/s10157-012-0688-1
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DOI: https://doi.org/10.1007/s10157-012-0688-1