Background: Because human leukocytes exhibit population and functional maturation differences in both T- and B-lymphocyte subsets, it is reasonable to expect that the response to immunosuppressive drugs such as cyclosporine (CsA) might also display age-related pharmacodynamics. Recently, we developed a reliable and precise method to measure clinically applicable surrogate pharmacodynamic markers for the action of CsA in vivo. The aim of this study was to determine a potential relationship between human ontogeny and the in vivo effect of CsA on the lymphocyte. Specifically, we characterized the concentration-related inhibitory effect of CsA on PMA/ionomycin-stimulated intracellular cytokine expression in peripheral blood lymphocytes obtained from paediatric and adult renal transplant patients covering a broad range of age. Method: We analyzed in a prospective study 184 renal allograft recipients in the maintenance period post-transplant, stratified according to age (< 18 years, N=31; 18-59 years, N=98; ≥ 60 years, N=55). CsA concentrations in whole blood were measured before and 2 hrs (C2) after oral drug intake. Gene expression of IL-2, IFN-g and GM-CSF was measured in PMA/ionomycin-stimulated peripheral blood lymphocytes by quantitative real-time PCR. To separate the effects of varying CsA concentrations from the impact of age, a CsA sensitivity index was calculated as index = log(100 - residual gene expression)/log (C2). Results: In univariate linear regression analysis statistically significant and apparently continuous relationships between age and the residual gene expression of IL-2, IFN- g and GM-CSF were observed. The CsA sensitivity index was significantly higher in younger patients, indicating higher sensitivity to the effect of CsA and, thus, stronger immunosuppression at a given CsA blood concentration. These age-related differences were more pronounced for IL-2 and IFN- g. Multiple linear regression analysis indicated an independent effect of age on residual IL-2 expression. This effect of age on predicted residual IL-2 expression was stronger at lower CsA C2 concentrations (Figure).[Fig. 1]Conclusion: This age-dependency of residual IL-2 expression indicates an enhanced sensitivity to CsA-induced suppression of intracellular IL-2 expression in paediatric patients. Hence, lymphocyte ontogeny corresponds to a variable and age-related response to CsA. This role of development not only on the disposition, but also on the action of CsA must be considered for the optimization of immunosuppressive therapy in paediatric patients.