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Clinical Chemistry 45: 1477-1484, 1999;
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(Clinical Chemistry. 1999;45:1477-1484.)
© 1999 American Association for Clinical Chemistry, Inc.

Articles

Inhibition of Stimulated Interleukin-2 Production in Whole Blood: A Practical Measure of Cyclosporine Effect

C. Michael Steina, John J. Murray and Alastair J.J. Wood

Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
a Address correspondence to this author at: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Medical Research Bldg., Room 560, Nashville, TN 37232-6602. Fax 615-343-2551; e-mail michael.stein{at}mcmail.vanderbilt.edu

Background: Prediction of cyclosporine (CSA) efficacy and toxicity in individual patients is difficult. There is no practical, biologically relevant, pharmacodynamic measure of CSA effect. A major effect of CSA is to decrease interleukin-2 (IL-2) production; however, measurement of this effect in isolated lymphocytes as a marker of response to CSA has been problematic.

Methods: CSA inhibition of phytohemagglutinin-P (PHA)-stimulated IL-2 production, measured by ELISA, was studied ex vivo in whole blood drawn before, and after subjects received 4 mg/kg oral CSA.

Results: Four hours after CSA was administered, the mean (± SD) CSA concentration was 702 ± 196 µg/L and PHA-stimulated IL-2 production decreased by 68.7% ± 17.2% (P <0.0001; n = 17). Twenty-four hours after CSA was administered, concentrations were low (64 ± 24 µg/L), with no inhibition of IL-2 production. A rapid, concentration-dependent response occurred. Maximum CSA concentrations (944 ± 187 µg/L) and maximum inhibition of IL-2 production (86.9% ± 13.7%) occurred 90 min after subjects received CSA. In vitro, 32.5–1200 µg/L CSA also inhibited PHA-stimulated IL-2 production in whole blood in a dose-dependent fashion with a similar IC50 (~300–400 µg/L) ex vivo and in vitro.

Conclusion: In the search for a pharmacodynamic marker to better guide immunosuppressive therapy, the relationship between this simple, biologically relevant measure of CSA effect and clinical outcome should be determined.




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