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标题: 在非活性患者恢复病毒特异性CD8 + T细胞被PD-1阻断的功能连接 [打印本页]

作者: StephenW    时间: 2014-11-16 10:27     标题: 在非活性患者恢复病毒特异性CD8 + T细胞被PD-1阻断的功能连接

Research Article
Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation

    Bertram Bengsch1, 2, 3, †,
    Bianca Martin1, 2, 3, †,
    Robert Thimme1, ,


doi:10.1016/j.jhep.2014.07.005

Background & Aims

The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.

Methods

98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.

Results

In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.

Conclusions

Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy.
Abbreviations

    HBV, hepatitis B virus;
    HBeAg, hepatitis B e antigen;
    HIV, human immunodeficiency virus;
    PD-1, programmed cell death protein 1;
    CTLA-4, cytotoxic T-lymphocyte protein 4;
    2B4, natural killer cell receptor 2B4;
    BTLA, B and T lymphocyte attenuator;
    Tim-3, T cell immunoglobulin mucin receptor 3;
    LCMV, lymphocytic choriomeningitis virus;
    KLRG1, killer cell lectin-like receptor subfamily G member 1;
    LAG-3, lymphocyte activation gene 3 protein;
    MFI, median fluorescence intensity

Keywords

    Virus-specific CD8+ T cells;
    T cell differentiation;
    T cell exhaustion;
    HBV;
    Inactive carrier;
    PD-1;
    Inhibitory receptors

    Corresponding author. Address: Uniklinik Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany. Tel.: +49 761 270 34040; fax: +49 761 270 36100.



    These authors contributed equally to this work.

作者: StephenW    时间: 2014-11-16 10:28

研究论文
的乙型肝炎病毒特异性CD8 + T细胞的功能由PD-1阻断在非活性载体患者恢复被连接到T细胞的分化

    伯特伦Bengsch1,2,3,†,
    比安卡Martin1,2,3,†,
    罗伯特Thimme1,


DOI:10.1016/ j.jhep.2014.07.005

背景与目的

几种抑制信号转导途径通过耗尽的HBV特异性CD8 + T细胞在慢性感染的上调被认为有助于病毒的持久性。抑制性受体的阻断振兴疲惫的T细胞功能是一种很有前途的新的治疗方法。然而,小的信息是可用的关于个体抑制通路对HBV特异性CD8 + T细胞衰竭和相对贡献的抑制性受体阻断对恢复T细胞功能在慢性HBV的影响。

Methods

98 HLA-A2 +的慢性感染患者进行分析体外对乙型肝炎病毒特异性CD8+ T细胞应答,多种抑制性受体和T细胞分化标记物的表达。的抑制性受体阻断靶向效果,PD-1,2B4,添-3,CTLA-4和BTLA进行了评估体外。

结果

在我们的研究中,先体外后体内HBV特异性的CD8 + T细胞应答优先确定在e抗原的患者具有低的ALT和低病毒载量(不活动载波)。我们观察到PD-1为主的抑制性受体表达的一个清晰的层次结构。为抑制性受体阻滞剂的反应是异类。相比其他抑制性受体的阻断,在PD-1通路阻断导致了强劲的增长函数。值得注意的是,对PD-1阻断了积极的作用是有联系的中间T细胞分化。

结论

尽管多种抑制性受体的由HBV特异性CD8 + T细胞,表达并响应于封锁表达支配由PD-1。然而,PD-1的表达并没有预测对封锁。相反,应对封锁与中间T细胞分化有关。这些发现对于我们的抑制性受体阻滞剂作为一种新的治疗策略的理解具有重要意义。
缩略语

    乙肝病毒,乙型肝炎病毒;
    大三阳,乙肝e抗原;
    艾滋病病毒,人类免疫缺陷病毒;
    PD-1,细胞程序性死亡蛋白1;
    CTLA-4的细胞,细胞毒性T淋巴细胞蛋白4;
    2B4,自然杀伤细胞受体2B4;
    BTLA,B和T淋巴细胞衰减器;
    TIM-3,T细胞免疫球蛋白粘蛋白受体3;
    LCMV,淋巴细胞性脉络丛脑膜炎病毒;
    KLRG1,杀伤细胞凝集素样受体亚家族ģ构件1;
    LAG-3,淋巴细胞活化基因3蛋白质;
    MFI,平均荧光强度

关键字

    病毒特异性CD8 + T细胞;
    T细胞分化;
    T细胞耗竭;
    乙肝病毒;
    不活动的载体;
    PD-1;
    抑制性受体

    Corresponding author。地址:Uniklinik弗赖堡,Hugstetter海峡。 55,79106德国弗赖堡。电话:+4976127034040;传真:+4976127036100。



    这些作者作出了贡献同样对这项的工作。
作者: 001话梅    时间: 2014-11-16 11:07

看不懂
作者: StephenW    时间: 2014-11-16 11:27

本帖最后由 StephenW 于 2014-11-16 11:29 编辑

回复 001话梅 的帖子




T细胞能攻击乙肝病毒感染的细胞,也能攻击癌细胞。然而,这些T细胞耗尽,他们有过多的PD-1受体在其表面上。
科学家发明抗体阻断这些受体。这已经在癌症治疗中已有成功完成。科学家们现在希望利用这些抗体来重新振兴T细胞攻击乙肝病毒感染的细胞. 这项研究旨在了解更多.




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