Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for tacrolimus.
Nuclear translocation of nuclear factor of activated T cells (NFAT) as a quantitative pharmacodynamic parameter for tacrolimus.
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DOI：
10.1002/cyto.a.22401
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发表时间：
2013-12
期刊：
影响因子：
3.7
通讯作者：
Minderman, Hans
中科院分区：
文献类型：
--
作者：
Maguire, Orla;Tornatore, Kathleen M.;O'Loughlin, Kieran L.;Venuto, Rocco C.;Minderman, Hans
活化T细胞核因子(NFAT)是一类参与免疫调节的转录因子家族。经典的NFAT途径是钙依赖的，激活后，NFAT被磷酸酶钙调神经磷酸酶去磷酸化。这导致它从细胞质转位到细胞核，并转录下游的靶基因，包括细胞因子IL-2、IL-10和干扰素γ。钙调神经磷酸酶抑制剂，包括他克莫司，可抑制NFAT途径，并在移植环境中用作免疫抑制剂，以防止移植排斥反应。到目前为止，还没有直接的手段来监测他克莫司的药效学。在这项研究中，基于图像细胞术的快速、定量的检测NFAT1核转位的方法被用来评估T细胞中NFAT的激活及其对他克莫司的抑制作用。在体外，NFAT1抑制和他克莫司剂量之间存在强烈的剂量依赖关系。他克莫司体内剂量前后稳定肾移植受者血浆中NFAT1抑制的时间动力学分析与他克莫司的预期药代动力学曲线相关。对患者自身的CD4和CD8 T细胞的分析进一步证实了这一点。这是首次报道通过核转位测量NFAT1激活电位可以作为他克莫司作用的直接、灵敏、可重复性和定量的药效学读数。这些结果，以及这种分析的快速周转时间，证明了它值得在更大的临床环境中进行评估，以评估其在钙调神经磷酸酶抑制剂的治疗药物监测中的作用。
Nuclear Factor of Activated T cells (NFAT) is a family of transcription factors involved in regulating the immune response. The canonical NFAT pathway is calcium-dependent and upon activation, NFAT is dephosphorylated by the phosphatase, calcineurin. This results in its translocation from the cytoplasm to the nucleus and transcription of downstream target genes that include the cytokines IL-2, IL-10, and IFNγ. Calcineurin inhibitors including tacrolimus inhibit the NFAT pathway and are used as immunosuppressants in transplant settings to prevent graft rejection. There is, as yet, no direct means to monitor tacrolimus pharmacodynamics. In this study, a rapid, quantitative, image cytometry–based measurement of nuclear translocation of NFAT1 is used to evaluate NFAT activation in T cells and its tacrolimus-induced inhibition. A strong dose-dependent correlation between NFAT1 inhibition and tacrolimus dose is demonstrated in vitro. Time kinetic analysis of NFAT1 inhibition in plasma from stable renal transplant recipients before and after an in vivo dose with tacrolimus correlated with the expected pharmacokinetic profile of tacrolimus. This was further corroborated by analysis of patients' autologous CD4 and CD8 T cells. This is the first report to show that the measurement of NFAT1 activation potential by nuclear translocation can be used as a direct, sensitive, reproducible and quantitative pharmacodynamic readout for tacrolimus action. These results, and the rapid turnaround time for this assay, warrant its evaluation in a larger clinical setting to assess its role in therapeutic drug monitoring of calcineurin inhibitors.
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影响因子：
6.2
作者：
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通讯作者：
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DOI：
10.1124/jpet.104.074930
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