Stimulated response of peripheral lymphocytes may distinguish cyclosporineeffect in renal transplant recipients receiving a cyclosporine plus rapamycin regimen

Background. Clinically, cyclosporine (CSA, Neoral) is titrated to concentra tions, and not to pharmacological effect. Methods. Intracellular interleukin- (IL) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry, after isolation from 14 renal transplant recipients receiving CSA+prednisone, and double-blind rapamycin (rapamycin:placebo=4:1). Results. The proportion (%) of CD4(+)IL-2(+) lymphocytes corresponding to C SA levels (mean+/-SD ng/ml) measured preoperatively (T0=0), and on postoper ative day 8, before (356+/-63), and 2 hr after the morning dose (C-max=1567 +/-669), decreased from 39+/-16 to 15+/-8 and 3+/-1.6, respectively. Recipr ocally, unresponsive lymphocytes (%CD4(+)IL-2(-)) increased with increasing CSA levels and predicted an EC,, of 249 ng/ml (CSA concentration at which CD4(+)IL-2(-) cells increased by 50% over baseline) in an E-max pharmacodyn amic model. Conclusions. Clinically, the pharmacological effect of CSA is quantifiable, and lies in the upper end of the predicted range. In our Neoral-treated sa mple population, C-max was associated with the least variable "cyclosporine effect." Such information could potentially individualize immunosuppressio n, and lead to rational dosing strategies.