Inhibition of stimulated interleukin-2 production in whole blood: a practical measure of cyclosporine effect.
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 microg/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 microg/L), with no inhibition of IL-2 production. A rapid, concentration-dependent response occurred. Maximum CSA concentrations (944 +/- 187 microg/L) and maximum inhibition of IL-2 production (86.9% +/- 13.7%) occurred 90 min after subjects received CSA. In vitro, 32.5-1200 microg/L CSA also inhibited PHA-stimulated IL-2 production in whole blood in a dose-dependent fashion with a similar IC(50) (approximately 300-400 microg/L) ex vivo and in vitro.


CONCLUSIONS
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.
Stein
C M
CM
Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA. michael.stein@mcmail.vanderbilt.edu
Murray
J J
JJ
Wood
A J
AJ
D015415:Biomarkers; D016572:Cyclosporine / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood*; D008297:Male; D010835:Phytohemagglutinins; D013997:Time Factors
D015415:Biomarkers; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; C028784:phytohemagglutinin-P; D016572:Cyclosporine