经过长期有效的核苷（酸）类似物治疗HBV特异性T细胞的功能

肝胆速递

http://www.gastrojournal.org/article/S0016-5085%2812%2900964-X/abstract?elsca1=etoc&elsca2=email&elsca3=0016-5085_201210_143_4&elsca4=gastroenterology
Restored Function of HBV-Specific T Cells After Long-term Effective Therapy With Nucleos(t)ide Analogues

Gastroenterology Volume 143, Issue 4 , Pages 963-973.e9, October 2012


    Carolina Boni    ,
    Diletta Laccabue    ,
    Pietro Lampertico    ,
    Tiziana Giuberti    ,
    Mauro Viganò    ,
    Simona Schivazappa    ,
    Arianna Alfieri    ,
    Marco Pesci    ,
    Giovanni B. Gaeta    ,
    Giuseppina Brancaccio    ,
    Massimo Colombo    ,
    Gabriele Missale    ,
    Carlo Ferrariemail address
  Affiliations
        First Division of Gastroenterology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
Received 26 October 2011; accepted 3 July 2012. published online 16 July 2012.

Background & Aims

In patients with chronic hepatitis B virus (HBV) infection, persistent exposure to high concentrations of antigen can disrupt T-cell functions. It is not clear to what extent long-term suppression of HBV by nucleos(t)ide analogues can restore antiviral T-cell functions. We compared HBV-specific T-cell responses of patients treated with nucleos(t)ide analogues with those detected in other conditions of HBV control.
Methods

We analyzed intracellular levels of interferon gamma, interleukin-2, and tumor necrosis factor α in HBV-specific T cells after 10 days of stimulation with peptides covering the overall HBV genotype D sequence and ex vivo with selected CD8 epitopes and the corresponding HLA-A2 dextramers. Findings from patients treated with nucleos(t)ide analogues who had complete (HBV DNA negative/antibody to hepatitis B surface antigen positive) or partial (HBV DNA negative/hepatitis B surface antigen positive) control of their infections were compared with those of patients with spontaneous or interferon alfa–induced resolution of acute or chronic infections, inactive HBV carriers, or untreated hepatitis B e antigen–negative patients with chronic infections.
Results

Although HBV-specific T cells from nucleos(t)ide analogue–treated patients with complete control of infection were dysfunctional ex vivo, they had efficient responses after in vitro expansion. These responses were comparable to those of patients who spontaneously resolved acute HBV infection. Nucleos(t)ide analogue–treated patients who were HBV DNA negative but hepatitis B surface antigen positive had lower levels of T-cell responses but responses greater than those of untreated patients with chronic infection.
Conclusions

In vitro reactivity can be restored to T cells from patients with suppressed HBV infection following long-term treatment with nucleos(t)ide analogues, despite prolonged exposure to large loads of antigen. Immune therapies that increase the antiviral T-cell response might increase the likelihood of complete HBV control in patients undergoing long-term nucleos(t)ide analogue treatment.

肝胆速递

经过长期有效的核苷（酸）类似物治疗HBV特异性T细胞的功能恢复

消化内科卷143，第4期，963-973.e9，2012年10月


    卡罗来纳州博尼，
    Diletta Laccabue，
    彼得Lampertico，
    TIZIANA Giuberti，
    毛罗VIGANO，
    西蒙娜Schivazappa，
    阿里安娜阿尔菲里，
    马可·派西，
    乔瓦尼·B.加埃塔，
    Giuseppina布兰卡乔，
    马西莫·科伦坡，
    加布里埃莱Missale，
    卡罗Ferrariemail地址

首先胃肠科，中基金会IRCCS CA的格兰达Policlinico，大学留学，Ospedale马焦雷教堂，米兰，意大利米兰STUDI
收稿二零一一年十月二十六日，2012年7月3日。 2012年7月16号在网上公布。

背景与目的

持久暴露于高浓度的抗原与慢性乙型肝炎病毒（HBV）感染的患者，可以破坏T细胞的功能。目前尚不清楚在何种程度上长期抑制HBV的核苷（酸）类似物抗病毒T细胞的功能恢复。我们比较了HBV特异性T细胞应答的患者治疗的核苷（酸）类似物与检测HBV控制的其他条件。
方法

我们分析了细胞内水平的干扰素γ，白细胞介素-2，和肿瘤坏死因子α在HBV特异性T细胞的刺激后10天与覆盖的整体HBV基因型D序列与ex vivo的与选定的CD8表位和相应的HLA-A2的肽dextramers。与核苷（酸）类似物有完整的（HBV DNA阴性/抗体，乙肝表面抗原阳性）或部分（HBV DNA阴性/ B型肝炎表面抗原阳性）控制其感染的患者进行了比较，发现患者急性或慢性感染，非活动性HBV携带者，或未经处理的B型肝炎e抗原阴性的慢性感染患者自发或干扰素α诱导的分辨率。
结果

虽然核苷（酸）类似物治疗的患者的完全控制受感染的HBV特异性T细胞功能的体外有效的反应后，他们在体外扩增。这些反应与自发地解决急性HBV感染的患者。核苷（酸）类似物治疗的患者HBV DNA阴性，但乙肝表面抗原阳性的T细胞反应，但反应比那些未经治疗的患者与慢性感染水平较低。
结论

在体外反应可以恢复到T细胞的抑制HBV感染的核苷（酸）类似物长期治疗的患者，尽管长期暴露在大负载抗原。在经历长期的核苷（酸）类似物治疗的患者，免疫疗法可能会增加，从而增加了抗病毒的T细胞反应的可能性完整的HBV控制。

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http://www.ihepa.com/ArticleView_5798.html
核苷（酸）类似物长期有效治疗可恢复HBV特异性T细胞功能
-----Restored Function of HBV-specific T Cells after Long-term Effective Therapy with Nucleos(t)ide Analogues
来源： 作者：国际肝病 发布时间：2012-9-18 14:26:37   阅读：93
　　持续暴露于高浓度抗原导致慢性乙型肝炎感染时T细胞功能低下，意大利帕尔玛大学医院Boni等的研究发现，用核苷（酸）类似物（nucleos(t)ide analogue，NA）长期治疗抑制病毒，特异性T细胞的活性在体外能够恢复。
　　研究人员从受试者体内分离HBV特异性T细胞，直接检测或在体外培养刺激后检测细胞内的IFN-γ、IL-2和TFN-α水平。结果显示，NA治疗后获得完全应答（HBV DNA阴性、抗-HBs阳性）的患者体内的HBV特异性T细胞在直接分离后存在功能障碍，但在体外扩增后能产生有效的应答，应答水平与急性HBV感染自发痊愈者相当。NA治疗后仅获得部分应答的患者有低水平的T细胞应答，但强于未治疗的慢性肝炎患者。
　　这项研究提示：增强抗病毒T细胞应答的免疫疗法或可帮助NA长期治疗的患者获得对病毒的完全控制。
　Gastroenterology. 2012 Jul，在线发表