Delayed Cytokine mRNA Expression Kinetics after T-Lymphocyte Costimulation: A Quantitative Measure of the Efficacy of Cyclosporin A-based Immunosuppression
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TLDR
A delayed increase in cytokine mRNA expression during T-cell costimulation may represent a sensitive effect of immunosuppression and the parameter "area of cytokineRNA expression over time", which should include absolute cytokine RNA values at two different time points of mRNA kinetics is suggested.Abstract:
Background: Because cyclosporin A (CsA) and glucocorticoids inhibit the production of interleukin-2 (IL-2) and other cytokines, quantitative analysis of cytokine mRNA might constitute a pharmacodynamic measure for immunosuppressive drug effects. We investigated whether immunosuppressive drugs influence cytokine mRNA expression kinetics during T-cell costimulation.
Methods: We used a human whole blood assay to determine basal (unstimulated) IL-2, IL-4, and tumor necrosis factor-α (TNF-α) mRNA concentrations and expression kinetics after anti-CD3/anti-CD28 monoclonal antibody costimulation in kidney transplant recipients undergoing CsA-based immunosuppressive triple therapy and in healthy controls (ex vivo study I). The effect of CsA on IL-2 mRNA expression kinetics was also determined ex vivo in patients undergoing CsA monotherapy (ex vivo study II) and after in vitro addition of CsA.
Results: In ex vivo study I, basal TNF-α mRNA but not IL-2 and IL-4 mRNA was decreased in kidney transplant patients. We observed shifts in peak IL-2 and IL-4 (from 8 to 24 h) and TNF-α (from 4 to 8 h of costimulation) mRNA expression in kidney transplant patients after T-cell costimulation. In patients undergoing CsA monotherapy (ex vivo study II), the inhibitory effect of CsA was detectable as an individually delayed increase in IL-2 mRNA during costimulation. In vitro addition of CsA also induced a dose-independent displacement of IL-2 mRNA expression kinetics (i.e., a delay).
Conclusions: A delayed increase in cytokine mRNA expression during T-cell costimulation may represent a sensitive effect of immunosuppression. The single analysis of one absolute or peak mRNA value could be misleading. For prospective studies involving measurement of cytokine mRNA, we therefore suggest the parameter “area of cytokine mRNA expression over time”, which should include absolute cytokine mRNA values at two different time points of mRNA kinetics.read more
Citations
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Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy : Second Consensus Report
Mercè Brunet,Teun van Gelder,Anders Åsberg,Vincent Haufroid,Vincent Haufroid,Dennis A. Hesselink,Loralie J. Langman,Florian Lemaitre,Pierre Marquet,Christoph Seger,Maria Shipkova,Alexander A. Vinks,Alexander A. Vinks,Pierre Wallemacq,Eberhard Wieland,Jean-Baptiste Woillard,Markus J. Barten,Klemens Budde,Helena Colom,Maja Theresa Dieterlen,Laure Elens,Kamisha L. Johnson-Davis,Paweł K. Kunicki,Iain MacPhee,Satohiro Masuda,Binu S. Mathew,Olga Millán,Tomoyuki Mizuno,Tomoyuki Mizuno,Dirk Jan A.R. Moes,Caroline Monchaud,Ofelia Noceti,Tomasz Pawinski,Nicolas Picard,Ron H.N. van Schaik,Claudia Sommerer,Nils Tore Vethe,Brenda C. M. de Winter,Uwe Christians,Stein Bergan +39 more
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Pharmacodynamic monitoring of cyclosporine a in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies.
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Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation
Mercè Brunet,Maria Shipkova,Teun van Gelder,Eberhard Wieland,Claudia Sommerer,Klemens Budde,Vincent Haufroid,Uwe Christians,Marcos López-Hoyos,Markus J. Barten,Stein Bergan,Nicolas Picard,Olga López,P. Marquet,D. A. Hesselink,Ofelia Noceti,Tomasz Pawinski,Pierre Wallemacq,Michael Oellerich +18 more
TL;DR: A group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials.
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