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T-Cell Function Monitoring in Stable Renal Transplant Patients Treated with Sirolimus Monotherapy

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Abstract

Background: Sirolimus is an agent with lymphocyte-specific features similar to those of calcineurin inhibitors but with a different mechanism of action and safety profile. To optimize the use of sirolimus-based immunosuppression, further investigation of appropriate pharmacokinetic (sirolimus exposure) and pharmacodynamic (sirolimus T-cell immunomodulator effect) monitoring is required to determine personalized target concentrations.

Aim: The main objective of the study was to evaluate the feasibility and reproducibility of combined pharmacokinetic and pharmacodynamic monitoring and to apply biomarkers of immunosuppression in stable kidney transplant recipients receiving sirolimus monotherapy.

Methods: Fourteen renal transplant patients treated with sirolimus monotherapy (median 2 years) were included in this study. Pharmacokinetic and pharmacodynamic parameters were evaluated in each patient three times: at inclusion in the study (day 1), then again at 3 and 6 months.

Results: The median sirolimus concentration was 11.5 ng/mL. CD4+ T-cell adenosine triphosphate (ATP) concentrations (150 ng/mL) and interleukin (IL)-10 production (50.9 ng/mL) were significantly lower in treated patients than in healthy controls (n = 95) [301 ng/mL; 278 ng/mL, respectively]. Median inhibition of T-cell proliferation was 60% (31–96%) in treated patients. Interferon-γ and transforming growth factor-β production was found to be similar to those in the healthy controls. Our results suggest an association between low ATP and IL-10 concentrations and the presence of infection.

Conclusions: The sequential measurement of these biomarkers in stable renal transplant recipients treated with monotherapy could be useful to evaluate the biological effect of sirolimus in each patient and to establish personalized therapy taking into account the individual response to the drug.

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References

  1. Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcome after renal transplantation. N Eng J Med 2002; 346: 580–90

    Article  Google Scholar 

  2. Flechner SM, Goldfarb D, Modlin Ch, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective randomized trial of SRL versus cyclosporine. Transplantation 2002; 74(8): 1070–6

    Article  PubMed  CAS  Google Scholar 

  3. Mathew T, Kreis H, Friend P. Two-years incidence of malignancy in sirolimustreated renal transplant recipients: results from five multicenter studies. Clin Transplant 2004; 18(4): 446–9

    Article  PubMed  Google Scholar 

  4. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignances. Transplantation 2005; 80(7): 883–9

    Article  PubMed  CAS  Google Scholar 

  5. Meier-Kriesche HU, Li S, Gruessner RW, et al. Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant 2006; 6 (Pt 2): 1111–31

    Article  PubMed  CAS  Google Scholar 

  6. Millán O, Brunet M, Campistol JM, et al. Pharmacodynamic approach to immunosuppressive therapies using calcineurin inhibitors and mycophenolate mofetil. Clin Chem 2003; 49(11): 1891–9

    Article  PubMed  Google Scholar 

  7. Brunet M, Martorell J, Oppenheimer F, et al. Pharmacokinetics and pharmacodynamics of mycophenolic acid in stable renal transplant recipients treated with low doses of mycophenolate mofetil. Transpl Int 2000; 13: S301–5

    PubMed  Google Scholar 

  8. Millán O, Oppenheimer F, Brunet M, et al. Assessment of mycophenolic acid-induced immunosuppression, a new approach. Clin Chem 2000; 46(9): 1376–83

    PubMed  Google Scholar 

  9. Diekmann F, Gutierrez-Dalmau A, Torregrosa J, et al. Sirolimus monotherapy: feasible immunosuppression for long-term follow-up of kidney transplantation: a pilot experience. Transplantation 2005 Nov 15; 80(9): 1344–8

    Article  PubMed  CAS  Google Scholar 

  10. Streit F, Armstrong V, Oellerich M. Rapid liquid chromatography-tandem mass spectrometry routine method for simultaneous determination of sirolimus, everolimus, tacrolimus and cyclosporine A in whole blood. Clin Chem 2002; 48(6): 955–8

    PubMed  CAS  Google Scholar 

  11. Millán O, Jiénez O, Fortuna V, et al. Role of FK778 or in combination with tacrolimus or mTOR inhibitors as an immunomodulator of immunofunctions: in vitro evaluation of T cell proliferation and the expression of lymphocyte surface antigens. Int J Immunophatol Pharmacol 2006; 19: 319–30

    Google Scholar 

  12. Barten MJ, Streit F, Boeger M, et al. Sinergistic effects of sirolimus with cyclosporine and tacrolimus: analysis of immunosuppression on lymphocyte proliferation and activation in rat whole blood. Transplantation 2004; 77(8): 1154–62

    Article  PubMed  CAS  Google Scholar 

  13. Burkhart C, Heusser C, Morris RE, et al. Pharmacodynamics in the development of new immunosuppressant drugs. Ther Drug Monit 2004; 26(6): 588–92

    Article  PubMed  CAS  Google Scholar 

  14. Klupp J, van Gelder T, Dambrin C, et al. Sustained suppression of peripheral blood immune functions by treatment with mycophenolate mofetil correlates with reduced severity of cardiac allograft rejection. J Heart Lung Transplant 2004; 23(3): 334–51

    Article  PubMed  Google Scholar 

  15. Kowalski R, Post D, Schneider MC, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant 2003; 17: 77–88

    Article  PubMed  Google Scholar 

  16. Valero R, Sanchez-Velasco P, Rodrigo E, et al. Assesment about risk of infection in kidney transplant by measuring the concentration of atp from CD4 cells following stimulation by Cylex [poster abstract 1244]. World Transplant Congress; 2006 Jul 22–27; Boston. Am J Transplant 2006; 6 Suppl. 2: 486

    Google Scholar 

  17. Böhler T, Nolting J, Kamar N, et al. Validation of immunological biomarkers for the pharmacodynamic monitoring of immunosuppessive drugs in humans. Ther Drug Monit 2007; 29(1): 77–86

    Article  PubMed  Google Scholar 

  18. Jorgensen PF, Wang JE, Almlöf M, et al. Sirolimus interferes with the innate response to bacterial products in human whole blood by attenuation of IL-10 production. Scand J Immunol 2001; 53: 184–91

    Article  PubMed  CAS  Google Scholar 

  19. Conti P, Kempuraj D, Kandere K, et al. IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol Lett 2003; 86: 123–9

    Article  PubMed  CAS  Google Scholar 

  20. Corinti S, Albanesi A, la Sala A, et al. Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol 2001; 166: 4312–8

    PubMed  CAS  Google Scholar 

  21. Prakken BJ, Wendling U, van der Zee R, et al. Induction of IL-10 and inhibition of experimental arthritis are specific features of microbial heat shock proteins that are absent for other evolutionarily conserved immunodominant proteins. J Immunol 2001; 167: 4147–53

    PubMed  CAS  Google Scholar 

  22. Fehérvari Z, Yamaguchi T, Sakaguchi S. The dichotomous role of IL-2: tolerance versus immunity. Trends Immunol 2006; 27(3): 109–11

    Article  PubMed  Google Scholar 

  23. Boleslawski E, Conti F, Sanquer S, et al. Defective inhibition of peripheral CD8+T cell IL-2 production by anti-calcineurin drugs during acute liver allograft rejection. Transplantation 2004; Jun 27; 77(12): 1815–20

    Article  PubMed  CAS  Google Scholar 

  24. Pankewycz O, Miao L, Isaacs R, et al. Increased renal tubular expression of transforming growth factor beta in human allografts correlates with cyclosporine toxicity. Kidney Int 1996; 50(5): 1634–40

    Article  PubMed  CAS  Google Scholar 

  25. Yang W, Gao W, Zhang D, et al. Combination of rapamycin plus mutant TGF-β/Fc to induce immune tolerance [abstract 42]. World Transplant Congress; 2006 Jul 22-27; Boston. Am J Transplant 2006; 6 Suppl. 2: 80

    Google Scholar 

  26. Dodge IL, Demirci G, Strom TB, et al. Rapamycin induces transforming growth factor-β production by lymphocytes. Transplantation 2000; 70(7): 1104–6

    Article  PubMed  CAS  Google Scholar 

  27. Chen YG, Liu F, Massagué J. Mechanism of TGF-β receptor inhibition by FKBP12. EMBO J 1997; 16: 3866–76

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was partially supported by a grant from the ed Nacional de Trasplante (Proyecto V-2003-REDC03F-0).

The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Laboratori de Farmacologia, Centre de Diagnòstic Biomèdic, IDIBAPS, Hospital Clínic de Barcelona University, C/ Villarroel 170, Barcelona, 08036, Spain

    Mercè Brunet, David Guillen & Olga Millán

  2. Unidad de Transplante Renal, IDIBAPS, Hospital Clínic, Barcelona University, Barcelona, Spain

    Josep Ma. Campistol & Fritz Diekmann

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  1. Mercè Brunet
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  2. Josep Ma. Campistol
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  3. Fritz Diekmann
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  4. David Guillen
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  5. Olga Millán
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Correspondence to Mercè Brunet.

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Brunet, M., Campistol, J.M., Diekmann, F. et al. T-Cell Function Monitoring in Stable Renal Transplant Patients Treated with Sirolimus Monotherapy. Mol Diag Ther 11, 247–256 (2007). https://doi.org/10.1007/BF03256246

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