Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection
Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection
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DOI：
10.1007/s00535-012-0667-z
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发表时间：
2013-05-01
影响因子：
6.3
通讯作者：
Takehara, Tetsuo
中科院分区：
文献类型：
--
作者：
Higashitani, Koyo;Kanto, Tatsuya;Takehara, Tetsuo
树突状细胞（dc）功能的改变和/或调节性T细胞（Tregs）的增加与慢性丙型肝炎病毒（HCV）感染的发病机制有关。一种色氨酸分解酶，吲哚胺2,3-双加氧酶（IDO），据报道是免疫耐受的诱导剂。我们的目的是澄清IDO是否在慢性丙型肝炎患者中被激活及其在免疫应答中的作用。这项研究招募了176名慢性HCV感染患者和37名健康志愿者。采用高效液相色谱法测定血清犬尿氨酸浓度，并分析其与临床参数的相关性。从受试者中制备单核细胞来源的dc，随后用脂多糖和干扰素- γ联合刺激诱导功能性IDO（定义为IDO- dc）。比较患者和健康志愿者的表型、犬尿氨酸或细胞因子的产生以及与ido - dc的t细胞反应。患者血清犬尿氨酸水平明显高于健康志愿者，且血清犬尿氨酸水平与组织活性或纤维化评分呈正相关。患者IDO- dc的IDO活性明显高于志愿者IDO- dc。此外，与志愿者相比，来自患者的ido - dc在体外诱导更多的treg，并且ido特异性抑制剂降低了ido - dc诱导treg的频率。慢性丙型肝炎患者全身IDO活性增强与肝脏炎症和纤维化程度相关。在对炎症刺激的反应中，患者的dc倾向于诱导treg，其中一些作用依赖于IDO。
Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses.This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers.The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor.Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.