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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients.
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P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients.

机译：P-糖蛋白（P-gp）在来自实体器官移植受者的外周T细胞亚群中上调。

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摘要

Immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids are substrates for the transmembrane multidrug resistance pump P-glycoprotein (P-gp). Experience in oncologyhas suggested that chronic exposure to P-gp substrates induces upregulation of P-gp activity, which could result in resistance to immunosuppressive drugs. The authors investigated P-gp function in CD4+ and CD8+ T cells from the peripheral blood of solid organ transplant recipients (SOTX). Subjects included 14 stable SOTX (10 liver, 4 lung) and 16 healthy controls. Four-color flow cytometry was used to simultaneously measure intracellular concentration of the fluorescent P-gp substrate Rhodamine 123 (Rh123) and surface expression of CD45RO (nominal memory/effector), CD45RA (naive), and either CD4 or CD8. P-glycoprotein function was measured by a dye efflux assay in which activity was inferred from a decrease in Rh123 fluorescence. CD4+ and CD8+ T cells from patients and control subjects eliminated Rh123, and this activity was inhibited by verapamil, a known P-gp substrate. CD8+ T cells had greater P-gp activity than CD4+ cells, and naive and transitional T cells displayed greater activity than memory T cells. Activity was bimodal in CD8+ CD45RO+ T cells, with a subset of these cells expressing the greatest P-gp activity. Patient CD8+ naive and transitional T cells had upregulated P-gp activity compared to control subjects. We conclude that (1) P-gp activityis significantly upregulated in specific T-cell subsets (CD8+/CD45RA+) in the peripheral blood of SOTX, and (2) the bimodal nature of P-gp response in CD8+ T cells complicates analysis of the effect of chronic administration of P-gp substrates to SOTX.
机译：免疫抑制剂如环孢菌素，他克莫司，西罗莫司和皮质类固醇是跨膜耐多药泵P-糖蛋白（P-gp）的底物。肿瘤学经验表明，长期暴露于P-gp底物会诱导P-gp活性上调，这可能导致对免疫抑制药物的耐药性。作者研究了来自实体器官移植受者（SOTX）外周血的CD4 +和CD8 + T细胞中的P-gp功能。受试者包括14个稳定的SOTX（10个肝，4个肺）和16个健康对照。使用四色流式细胞术同时测量荧光P-gp底物若丹明123（Rh123）的细胞内浓度和CD45RO（名义记忆/效应子），CD45RA（纯天然）以及CD4或CD8的表面表达。 P-糖蛋白功能通过染料流出测定法进行测量，其中活性是根据Rh123荧光强度的降低来推断的。来自患者和对照组的CD4 +和CD8 + T细胞消除了Rh123，这种活性被维拉帕米（一种已知的P-gp底物）抑制。 CD8 + T细胞比CD4 +细胞具有更高的P-gp活性，而幼稚和过渡性T细胞则比记忆T细胞具有更高的活性。在CD8 + CD45RO + T细胞中，活性是双峰的，其中一部分细胞表达最大的P-gp活性。与对照受试者相比，患者CD8 +幼稚和过渡性T细胞的P-gp活性上调。我们得出的结论是：（1）SOTX外周血中特定的T细胞亚群（CD8 + / CD45RA +）中P-gp活性显着上调，并且（2）CD8 + T细胞中P-gp应答的双峰性质使对TTX的分析变得复杂长期向SOTX施用P-gp底物的效果。

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