Altered Thymic Function during Interferon Therapy in HCV-Infected Patients
Altered Thymic Function during Interferon Therapy in HCV-Infected Patients
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DOI：
10.1371/journal.pone.0034326
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发表时间：
2012-04-16
期刊：
影响因子：
3.7
通讯作者：
Cheynier, Remi
中科院分区：
文献类型：
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作者：
Beq, Stephanie;Rozlan, Sandra;Cheynier, Remi
干扰素治疗虽然在治疗丙型肝炎病毒感染方面有很好的效果，但会导致主要的副作用，特别是诱导强烈的外周T细胞淋巴细胞减少。我们在这里分析了干扰素α治疗对处于丙型肝炎病毒感染急性期或慢性期患者以及HIV/丙型肝炎病毒混合感染患者的胸腺功能和外周T细胞稳态的早期影响。在干扰素治疗开始后的前4个月，用流式细胞仪检测T细胞亚群的演变和T细胞的稳态，同时通过T细胞受体切除环(TREC)的定量和胸腺内前体T细胞的增殖来测定胸腺功能。从治疗的第一个月开始，所有T细胞亚群，包括原始T细胞和最近的胸腺移居者(RTE)，都观察到严重的淋巴细胞减少，与胸腺内前体T细胞的增殖抑制有关。随着淋巴细胞减少的进展，白介素7的血浆浓度迅速下降。这既不是细胞因子消耗增加的结果，也不是由于其被可溶性CD127中和所致。在IFNA治疗下，IL-7血浆浓度的下降与丙型肝炎病毒载量、胸腺活性和血液中RTE浓度的下降有关。这些数据表明，基于干扰素的治疗迅速影响胸腺生成，从而扰乱T细胞的稳态。这种副作用可能不利于干扰素α治疗的继续，并可能导致感染风险增加，特别是在艾滋病毒/丙型肝炎合并感染的患者中。综上所述，本研究提示IL-7在维持干扰素α治疗患者的外周T细胞稳态方面的治疗潜力。
Interferon alpha (IFN alpha) therapy, despite good efficacy in curing HCV infection, leads to major side effects, in particular inducement of a strong peripheral T-cell lymphocytopenia. We here analyze the early consequences of IFN alpha therapy on both thymic function and peripheral T-cell homeostasis in patients in the acute or chronic phase of HCV-infection as well as in HIV/HCV co-infected patients. The evolution of T-cell subsets and T-cell homeostasis were estimated by flow cytometry while thymic function was measured through quantification of T-cell receptor excision circles (TREC) and estimation of intrathymic precursor T-cell proliferation during the first four months following the initiation of IFN alpha therapy. Beginning with the first month of therapy, a profound lymphocytopenia was observed for all T-cell subsets, including naive T-cells and recent thymic emigrants (RTE), associated with inhibition of intrathymic precursor T-cell proliferation. Interleukin (IL)-7 plasma concentration rapidly dropped while lymphocytopenia progressed. This was neither a consequence of higher consumption of the cytokine nor due to its neutralization by soluble CD127. Decrease in IL-7 plasma concentration under IFNa therapy correlated with the decline in HCV viral load, thymic activity and RTE concentration in blood. These data demonstrate that IFN alpha-based therapy rapidly impacts on thymopoiesis and, consequently, perturbs T-cell homeostasis. Such a side effect might be detrimental for the continuation of IFN alpha therapy and may lead to an increased level of infectious risk, in particular in HIV/HCV co-infected patients. Altogether, this study suggests the therapeutic potential of IL-7 in the maintenance of peripheral T-cell homeostasis in IFN alpha-treated patients.