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Clinical Chemistry 48: 2225-2231, 2002;
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(Clinical Chemistry. 2002;48:2225-2231.)
© 2002 American Association for Clinical Chemistry, Inc.

Delayed Cytokine mRNA Expression Kinetics after T-Lymphocyte Costimulation: A Quantitative Measure of the Efficacy of Cyclosporin A-based Immunosuppression

Christoph Härtel1, Lutz Fricke2, Nina Schumacher1, Holger Kirchner1 and Michael Müller-Steinhardt1

1 Institute of Immunology and Transfusion Medicine, and
2 Department of Transplantation Medicine, University of Lübeck Medical School, Ratzeburger Allee 160, 23538 Lübeck, Germany.

aAuthor for correspondence. Fax 49-451-500-2857; e-mail muellerst{at}immu.mu-luebeck.de.

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-{alpha} (TNF-{alpha}) 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-{alpha} 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-{alpha} (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.




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