Calcineurin inhibitors differentially alter the circadian rhythm of T-cell functionality in transplant recipients

Journal of Translational Medicine

Urban Sester²  Martina Sester⁴  Danilo Fliser²  Hashim Abdul-Khaliq¹  Stephan Thijssen³  Kai van Bentum⁴  Karin Budich⁴  Sarah Leyking⁴ 

[1]Department of Paediatric Cardiology, Saarland University, Homburg, Germany

[2]Department of Internal Medicine IV, Saarland University, Homburg, Germany

[3]Current affiliation: Renal Research Institute, New York, USA

[4]Department of Transplant and Infection Immunology, Saarland University, Homburg, D-66421, Germany

关键词: Pharmacodynamics;    Pharmacokinetics;    Immunosuppression;    Cyclosporine A;    Tacrolimus;    Calcineurin inhibitor;    Kidney transplantation;    Whole blood assay;    Flow-cytometry;    T-cell reactivity;    Circadian rhythm;   

Others  :  1137570
DOI  :  10.1186/s12967-015-0420-5

 received in 2014-08-27, accepted in 2015-01-27,  发布年份 2015

【 摘 要 】

Background

Graft survival in transplant recipients depends on pharmacokinetics and on individual susceptibility towards immunosuppressive drugs. Nevertheless, pharmacodynamic changes in T-cell functionality in response to drugs and in relation to pharmacokinetics are poorly characterized. We therefore investigated the immunosuppressive effect of calcineurin inhibitors and steroids on general T-cell functionality after polyclonal stimulation of whole blood samples.

Methods

General T-cell functionality in the absence or presence of immunosuppressive drugs was determined in vitro directly from whole blood based on cytokine induction after stimulation with the polyclonal stimulus Staphylococcus aureus enterotoxin B. In addition, diurnal changes in leukocyte and lymphocyte subsets, and on T-cell function after intake of immunosuppressive drugs were analyzed in 19 patients during one day and compared to respective kinetics in six immunocompetent controls. Statistical analysis was performed using non-parametric and parametric tests.

Results

Susceptibility towards calcineurin inhibitors showed interindividual differences. When combined with steroids, tacrolimus led to more pronounced increase in the inhibitory activity as compared to cyclosporine A. While circadian alterations in leukocyte subpopulations and T-cell function in controls were related to endogenous cortisol levels, T-cell functionality in transplant recipients decreased after intake of the morning medication, which was more pronounced in patients with higher drug-dosages. Interestingly, calcineurin inhibitors differentially affected circadian rhythm of T-cell function, as patients on cyclosporine A showed a biphasic decrease in T-cell reactivity after drug-intake in the morning and evening, whereas T-cell reactivity in patients on tacrolimus remained rather stable.

Conclusions

The whole blood assay allows assessment of the inhibitory activity of immunosuppressive drugs in clinically relevant concentrations. Circadian alterations in T-cell function are determined by dose and type of immunosuppressive drugs and show distinct differences between cyclosporine A and tacrolimus. In future these findings may have practical implications to estimate the net immunosuppressive effect of a given drug-regimen that daily acts in an individual patient, and may contribute to individualize immunosuppression.

【 授权许可】

   
2015 Leyking et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Sommerer C, Giese T, Meuer S, Zeier M: Pharmacodynamic monitoring of calcineurin inhibitor therapy: is there a clinical benefit? Nephrol Dial Transplant 2009, 24(1):21-7.
• [2]van Rossum HH, de Fijter JW, van Pelt J: Pharmacodynamic monitoring of calcineurin inhibition therapy: principles, performance, and perspectives. Ther Drug Monit 2010, 32(1):3-10.
• [3]Egli A, Kohli S, Dickenmann M, Hirsch HH: Inhibition of polyomavirus BK-specific T-Cell responses by immunosuppressive drugs. Transplantation 2009, 88(10):1161-8.
• [4]Sester U, Gärtner BC, Wilkens H, Schwaab B, Wössner R, Kindermann I, et al.: Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant 2005, 5(6):1483-9.
• [5]Sester U, Wilkens H, van Bentum K, Singh M, Sybrecht GW, Schäfers HJ, et al.: Impaired detection of Mycobacterium tuberculosis immunity in patients using high levels of immunosuppressive drugs. Eur Respir J 2009, 34(3):702-10.
• [6]Kirsch S, Thijssen S, Alarcon Salvador S, Heine GH, van Bentum K, Fliser D, et al.: T-cell numbers and antigen-specific T-cell function follow different circadian rhythms. J Clin Immunol 2012, 32(6):1381-9.
• [7]Sester M, Sester U, Gärtner B, Heine G, Girndt M, Mueller-Lantzsch N, et al.: Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation 2001, 71(9):1287-94.
• [8]Fuller CL, Braciale VL: Selective induction of CD8+ cytotoxic T lymphocyte effector function by staphylococcus enterotoxin B. J Immunol 1998, 161(10):5179-86.
• [9]Rödström KE, Elbing K, Lindkvist-Petersson K: Structure of the superantigen staphylococcal enterotoxin B in complex with TCR and peptide-MHC demonstrates absence of TCR-peptide contacts. J Immunol 2014, 193(4):1998-2004.
• [10]Dimitrov S, Benedict C, Heutling D, Westermann J, Born J, Lange T: Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 2009, 113(21):5134-43.
• [11]Breinig T, Sester M, Sester U, Meyerhans A: Antigen-specific T cell responses: Determination of their frequencies, homing properties, and effector functions in human whole blood. Methods 2006, 38(2):77-83.
• [12]Shibata N, Shimakawa H, Minouchi T, Yamaji A: Erythrocyte uptake and protein binding of cyclosporin A (CyA) in human blood: factors affecting CyA concentration in erythrocytes. Biol Pharm Bull 1993, 16(7):702-7.
• [13]Lensmeyer GL, Wiebe DA, Carlson IH: Distribution of cyclosporin A metabolites among plasma and cells in whole blood: effect of temperature, hematocrit, and metabolite concentration. Clin Chem 1989, 35(1):56-63.
• [14]Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al.: Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007, 357(25):2562-75.
• [15]de Jonge H, Naesens M, Kuypers DR: New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit 2009, 31(4):416-35.
• [16]Naesens M, Kuypers DR, Sarwal M: Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009, 4(2):481-508.
• [17]Sandrini S, Aslam N, Tardanico R, Setti G, Bossini N, Valerio F, et al.: Tacrolimus versus cyclosporine for early steroid withdrawal after renal transplantation. J Nephrol 2012, 25(1):43-9.
• [18]Tornatore KM, Reed K, Venuto R: 24-hour immunologic assessment of CD4+ and CD8+ lymphocytes in renal transplant recipients receiving chronic methylprednisolone. Clin Nephrol 1995, 44(5):290-8.
• [19]Iwahori T, Takeuchi H, Matsuno N, Johjima Y, Konno O, Nakamura Y, et al.: Pharmacokinetic differences between morning and evening administration of cyclosporine and tacrolimus therapy. Transplant Proc 2005, 37(4):1739-40.
• [20]Baraldo M, Furlanut M: Chronopharmacokinetics of ciclosporin and tacrolimus. Clin Pharmacokinet 2006, 45(8):775-88.
• [21]Curtis JJ, Jones P, Barbeito R: Large within-day variation in cyclosporine absorption: circadian variation or food effect? Clin J Am Soc Nephrol 2006, 1(3):462-6.
• [22]Min DI, Chen HY, Fabrega A, Ukah FO, Wu YM, Corwin C, et al.: Circadian variation of tacrolimus disposition in liver allograft recipients. Transplantation 1996, 62(8):1190-2.
• [23]Christiaans M, van Duijnhoven E, Beysens T, Undre N, Schafer A, van Hooff J: Effect of breakfast on the oral bioavailability of tacrolimus and changes in pharmacokinetics at different times posttransplant in renal transplant recipients. Transplant Proc 1998, 30(4):1271-3.
• [24]Milano G, Chamorey AL: Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics. Chronobiol Int 2002, 19(1):177-89.
• [25]Lemmer B, Nold G, Behne S, Kaiser R: Chronopharmacokinetics and cardiovascular effects of nifedipine. Chronobiol Int 1991, 8(6):485-94.
• [26]Reinberg A, Pauchet F, Ruff F, Gervais A, Smolensky MH, Levi F, et al.: Comparison of once-daily evening versus morning sustained-release theophylline dosing for nocturnal asthma. Chronobiol Int 1987, 4(3):409-19.
• [27]Hosomi N, Sueda Y, Masugata H, Dobashi H, Murao K, Ueno M, et al.: The optimal timing of antihypertensive medication administration for morning hypertension in patients with cerebral infarction. Hypertens Res 2012, 35(7):720-4.
• [28]Ohdo S: Chronotherapeutic strategy: Rhythm monitoring, manipulation and disruption. Adv Drug Deliv Rev 2010, 62(9–10):859-75.
• [29]Ratte J, Halberg F, Kuhl JF, Najarian JS: Circadian variation in the rejection of rat kidney allografts. Surgery 1973, 73(1):102-8.
• [30]Cavallini M, Halberg F, Tao L, Sutherland DE: Circadian stage-dependent prolongation by cyclosporine of segmental pancreatic allograft function in the rat. Eur Surg Res 1986, 18(6):375-82.
• [31]Sester M, Gärtner BC, Sester U: Monitoring of CMV specific T-cell levels after organ transplantation. J Lab Med 2008, 32(3):121-30.
• [32]Mack U, Migliori GB, Sester M, Rieder HL, Ehlers S, Goletti D, et al.: LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement. Eur Respir J 2009, 33(5):956-73.
• [33]Egli A, Binet I, Binggeli S, Jaeger C, Dumoulin A, Schaub S, et al.: Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients. J Transl Med 2008, 6(1):29. BioMed Central Full Text
• [34]Heidt S, Roelen DL, Eijsink C, Eikmans M, van Kooten C, Claas FH, et al.: Calcineurin inhibitors affect B cell antibody responses indirectly by interfering with T cell help. Clin Exp Immunol 2010, 159(2):199-207.