title: Calcineurin inhibitors differentially alter the circadian rhythm of T-cell functionality in transplant recipients.
abstract: 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.
authors.affiliation: Department of Internal Medicine IV, Saarland University, Homburg, Germany. Sarah.leyking@uks.eu.|Department of Transplant and Infection Immunology, Saarland University, D-66421, Homburg, Germany. Sarah.leyking@uks.eu.
authors.forename: Sarah
authors.initials: S
authors.lastname: Leyking
authors.affiliation: Department of Transplant and Infection Immunology, Saarland University, D-66421, Homburg, Germany. karinka.b@gmx.de.
authors.forename: Karin
authors.initials: K
authors.lastname: Budich
authors.affiliation: Department of Internal Medicine IV, Saarland University, Homburg, Germany. K.van-Bentum@gmx.net.|Department of Transplant and Infection Immunology, Saarland University, D-66421, Homburg, Germany. K.van-Bentum@gmx.net.
authors.forename: Kai
authors.initials: K
authors.lastname: van Bentum
authors.affiliation: Department of Transplant and Infection Immunology, Saarland University, D-66421, Homburg, Germany. sthijssen@rriny.com.|Current affiliation: Renal Research Institute, New York, USA. sthijssen@rriny.com.
authors.forename: Stephan
authors.initials: S
authors.lastname: Thijssen
authors.affiliation: Department of Paediatric Cardiology, Saarland University, Homburg, Germany. hashim.abdul-khaliq@uks.eu.
authors.forename: Hashim
authors.initials: H
authors.lastname: Abdul-Khaliq
authors.affiliation: Department of Internal Medicine IV, Saarland University, Homburg, Germany. danilo.fliser@uks.eu.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: Department of Transplant and Infection Immunology, Saarland University, D-66421, Homburg, Germany. martina.sester@uks.eu.
authors.forename: Martina
authors.initials: M
authors.lastname: Sester
authors.affiliation: Department of Internal Medicine IV, Saarland University, Homburg, Germany. urban.sester@uks.eu.
authors.forename: Urban
authors.initials: U
authors.lastname: Sester
mesh_terms: D000328:Adult; D000368:Aged; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D002940:Circadian Rhythm / Q000187:drug effects*; D016572:Cyclosporine / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis; D003710:Demography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013256:Steroids / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016559:Tacrolimus / Q000627:therapeutic use; D066027:Transplant Recipients
chemical_list: D065095:Calcineurin Inhibitors; D016207:Cytokines; D013256:Steroids; D016572:Cyclosporine; D016559:Tacrolimus