慢性乙型肝炎患者T细胞功能在使用基于干扰素联合疗法治疗

StephenW

J Hepatol. 2015 Oct 23. pii: S0168-8278(15)00712-6. doi: 10.1016/j.jhep.2015.10.013. [Epub ahead of print]
Restoration of T cell function in chronic hepatitis B patients upon treatment with interferon based combination therapy.de Niet A1, Stelma F1, Jansen L1, Sinnige MJ2, Remmerswaal EB2, Takkenberg RB3, Kootstra NA2, Reesink HW4, van Lier RA5, van Leeuwen EM2.
Author information

• 1Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam; Department of Experimental Immunology, Academic Medical Center, Amsterdam.
• 2Department of Experimental Immunology, Academic Medical Center, Amsterdam.
• 3Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam.
• 4Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam; Department of Experimental Immunology, Academic Medical Center, Amsterdam. Electronic address: [email protected].
• 5Department of Experimental Immunology, Academic Medical Center, Amsterdam; Sanquin Blood Supply Foundation, Amsterdam.
  

AbstractBACKGROUND & AIMS: Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies.
METHODS: In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000 IU/mL) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182 IU/mL) treated with peginterferon/adefovir combination therapy who had various treatment outcomes.
RESULTS: HBV-specific T cells could be detected directly ex vivo in 7/22 patients with low viral load. These showed an early differentiated memory phenotype with reduced ability to produce IL-2 and cytotoxic molecules such as granzyme B and perforin, but with strong proliferative potential. In a cohort of 28 chronic hepatitis B patients with high viral load treated with peg-interferon and adefovir, HBV-specific T cells could not be detected direct ex vivo. However, HBV-specific T cells could be selectively expanded in vitro in patients with therapy induced HBsAg clearance (HBsAg loss n=7), but not in patients without HBsAg clearance (n=21). Further analysis of HBV-specific T cell function with peptide pools showed broad and efficient antiviral responses after therapy.
CONCLUSIONS: Our results show that peg-interferon based combination therapy can induce HBV-specific T cell restoration. These findings may help to develop novel therapeutic strategies to reconstitute antiviral functions and enhance viral clearance.
Copyright © 2015. Published by Elsevier B.V.


KEYWORDS: Adaptive immunity; Combination therapy; HBV-specific T cells; HBsAg loss; Hepatitis B

StephenW

肝脏病学杂志。 2015年十月23 PII：S0168-8278（15）00712-6。 DOI：10.1016 / j.jhep.2015.10.013。 [打印EPUB提前]
慢性乙型肝炎患者T细胞功能在使用基于干扰素联合疗法治疗恢复。
德Niet的A1，Stelma F1，扬森L1，Sinnige MJ2，Remmerswaal EB2，Takkenberg RB3，Kootstra NA2，Reesink HW4，面包车利尔RA5，货车Leeuwen EM2。
作者信息

    教研室胃肠病学和肝病学术医疗中心，阿姆斯特丹;实验免疫学，医学学术中心，阿姆斯特丹系。
    教研室实验免疫学，医学学术中心，阿姆斯特丹。
    3Department胃肠病学和肝病学术医疗中心，阿姆斯特丹。
    4Department胃肠病学和肝病学术医疗中心，阿姆斯特丹;实验免疫学，医学学术中心，阿姆斯特丹系。电子地址：[email protected]。
    5Department实验免疫学，医学学术中心，阿姆斯特丹; Sanquin血液供应基金会，阿姆斯特丹。

抽象的
背景与目的：

慢性乙型肝炎病毒（HBV）感染的特征在于HBV特异性T细胞的功能障碍。了解背后的T细胞功能障碍和恢复机制是优化治疗策略的发展具有重要意义。
方法：

在这项研究中，我们首先分析HBV特异性T细胞的患者的表型和功能与低病毒载量（HBV DNA <20000 IU / mL）和在病毒自发控制。接着，我们评估HBV特异性T细胞的患者的高病毒载量（HBV DNA> 17182 IU / mL）的聚乙二醇干扰素/阿德福韦组合疗法谁了各种处理结果进行处理。
结果：

可以在7/22患者病毒载量低直接离体检测HBV特异性T细胞。这些结果显示与产生IL-2和细胞毒性分子，例如粒酶B和穿孔，但具有很强的增殖潜力的能力降低的早期分化的记忆表型。在28慢性乙型肝炎患者的高病毒载量与PEG-干扰素和阿德福韦处理的队列中，HBV特异性T细胞不能检测直接离体。然而，HBV特异性T细胞可以选择性地在体外扩增的患者治疗引起的HBsAg清除（HBsAg消失N = 7），但不能在患者无HBsAg清除（21例）。用肽合并HBV特异性T细胞功能进一步分析显示治疗后广泛有效的抗病毒反应。
结论：

我们的研究结果表明，聚乙二醇干扰素为基础的联合疗法可诱导HBV特异性T细胞的恢复。这些发现可能有助于开发新的治疗策略，以重建抗病毒功能和增强病毒清除。

版权所有©2015年出版由Elsevier B.V.
关键词：

自适应免疫力;联合治疗; HBV特异性T细胞; HBsAg消失; B型肝炎