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Calcineurin inhibitors differentially alter the circadian rhythm of T-cell functionality in transplant recipients.
- Source :
-
Journal of translational medicine [J Transl Med] 2015 Feb 06; Vol. 13, pp. 51. Date of Electronic Publication: 2015 Feb 06. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Aged
Cyclosporine therapeutic use
Cytokines biosynthesis
Demography
Female
Humans
Male
Middle Aged
Steroids therapeutic use
Tacrolimus therapeutic use
Calcineurin Inhibitors pharmacology
Circadian Rhythm drug effects
T-Lymphocytes drug effects
T-Lymphocytes immunology
Transplant Recipients
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 25885792
- Full Text :
- https://doi.org/10.1186/s12967-015-0420-5