环孢素(CsA)药效学个体差异大，传统用药策略通过监测外周血CsA浓度来优化移植患者的治疗效果。临床实践却发现外周血CsA水平并不能很好地反映CsA药效。由于作用于T淋巴细胞，胞内CsA浓度与其疗效更相关。文献调研发现T淋巴细胞内CsA浓度与ABCB1基因mRNA表达量显著相关，而人结肠上皮细胞中ABCB1 mRNA的表达量又受到ABCB1基因甲基化的负调控。我们的前期研究发现肾移植患者术后淋巴细胞内ABCB1基因甲基化程度也存在个体差异。据此我们提出假说：T淋巴细胞内ABCB1基因甲基化通过改变ABCB1 mRNA表达量，调控胞内CsA浓度，从而引起CsA药效学差异。本研究拟从临床及细胞水平明确T细胞内CsA浓度与其药效学差异的关系；阐明ABCB1表达量与T细胞内CsA浓度的相关性；揭示ABCB1基因甲基化改变T细胞内CsA浓度的作用机制，为CsA个体化用药提供新思路。

Cyclosporine (CsA) is characterized by a high inter-individual pharmacokinetics variability. Hence, monitoring CsA concentrations in peripheral blood is recommended to optimize transplant patient’s outcome in traditional medical strategies. However, it indicated that peripheral blood CsA concentrations failed to reflect the drug effectiveness. It seems reasonable to assume that CsA concentrations at the target sites (intra-lymphocytes) are more relevant than peripheral blood concentrations in predicting treatment efficacy. A significantly negative correlation between ABCB1 mRNA expression and intracellular CsA concentrations in lymphocytes was reported, and a high methylation level of the ABCB1 was reported to down-regulate the ABCB1 mRNA expression in colonic epithelial cells. Our previous study showed that the methylation level of ABCB1 in lymphocytes also showed a significant inter-individual variation within renal transplant recipients. In the present project, the relationship of CsA concentrations in T-lymphocytes with the drug action and ABCB1 expression will be researched. Then the molecule mechanism of CsA concentrations adjusted through ABCB1 methylation in T-lymphocytes will be elucidated. The purpose of the project is providing a new method for individual medicine of CsA in renal transplant recipients.