免疫细胞反应并不需要诱导聚乙二醇化α-干扰素给药期间

StephenW

Journal of Hepatology

Volume 60, Issue 3, March 2014, Pages 500–507
Cover image
Research Article
Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration

    Lena Allweiss1,
    Tassilo Volz1,
    Marc Lütgehetmann1, 2,
    Katja Giersch1,
    Till Bornscheuer1,
    Ansgar W. Lohse1, 3,
    Joerg Petersen4,
    Han Ma5,
    Klaus Klumpp5,
    Simon P. Fletcher5, †,
    Maura Dandri1, 3, Corresponding author contact information, E-mail the corresponding author


Background & Aims

Pegylated interferon-alpha (PegIFNα) remains an attractive treatment option for chronic hepatitis B virus (HBV) infection because it induces higher rates of antigen loss and seroconversion than treatment with polymerase inhibitors. Although early HBsAg decline is recognised as the best predictor of sustained response to IFN-based therapy, it is unclear whether immune cell functions are required to induce significant antigenemia reduction in the first weeks of treatment. Aim of the study was to investigate whether PegIFNα can induce sustained human hepatocyte responsiveness and substantial loss of circulating and intrahepatic viral antigen loads in a system lacking immune cell functions.
Methods

HBV-infected humanized uPA/SCID mice received either PegIFNα, entecavir (ETV), or both agents in combination. Serological and intrahepatic changes were determined by qRT-PCR and immunohistochemistry and compared to untreated mice.
Results

After 4 weeks of treatment, median viremia reduction was greater in mice treated with ETV (either with or without PegIFNα) than with PegIFNα. In contrast, levels of circulating HBeAg, HBsAg, and intrahepatic HBcAg were significantly reduced (p = 0.03) only in mice receiving PegIFNα alone or in combination, as compared to mice receiving ETV monotherapy. Progressive antigen reduction was also demonstrated in mice receiving PegIFNα for 12 weeks (HBeAg = Δ1 log; HBsAg = Δ1.4 log; p <0.0001). Notably, repeated administrations of the longer-active PegIFNα could breach the impairment of HBV-infected hepatocyte responsiveness and induce sustained enhancement of human interferon stimulated genes (ISG).
Conclusions

The antiviral effects of PegIFNα exerted on the human hepatocytes can induce sustained responsiveness and trigger substantial HBV antigen decline without claiming the involvement of immune cell responses.
Keywords

    cccDNA;
    HBsAg;
    HBeAg;
    Interferon stimulated genes;
    Hepatocyte responsiveness;
    Humanized mice

Corresponding author contact information
    Corresponding author. Address: I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-, 20246 Hamburg, Germany. Tel.: +49 40 7410 52949; fax: +49 40 7410 57232.

†

    Present address: Gilead Sciences, Foster City, CA, USA.

Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier Ireland Ltd. All rights reserved.

StephenW

中华肝脏病杂志

第60卷，第3期， 2014年3月，页500-507
封面图片
研究论文
免疫细胞反应并不需要诱导的聚乙二醇化α-干扰素给药期间大幅乙型肝炎病毒抗原下降

    莉娜Allweiss1 ，
    塔西洛Volz1 ，
    马克Lütgehetmann1 ，2，
    卡佳Giersch1 ，
    直到Bornscheuer1 ，
    Ansgar的W. Lohse1 ， 3 ，
    约尔格Petersen4 ，
    韩MA5 ，
    克劳斯Klumpp5 ，
    西蒙体育Fletcher5 ， † ，
    莫拉Dandri1 ， 3 ，通讯作者的联系信息，电子邮件通讯作者


http://dx.doi.org/10.1016/j.jhep.2013.10.021
   
背景及宗旨

聚乙二醇化干扰素-α （ PegIFNα ）仍然是慢性乙型肝炎病毒（ HBV）感染一个有吸引力的治疗选择，因为它诱使抗原消失和血清转换率比用聚合酶抑制剂治疗。虽然早期的HBsAg下降被认为是对干扰素为基础的治疗持续应答的最好的预测，目前还不清楚免疫细胞的功能是否需要诱导治疗的第一个星期显著抗原减少。这项研究的目的是调查PegIFNα是否能诱导持久的人类肝细胞的反应和循环和肝内病毒抗原负载的系统中缺乏免疫细胞功能的重大损失。
方法

HBV感染的人源化的uPA / SCID小鼠分别接受PegIFNα ，恩替卡韦（ETV） ，或结合这两种药物。血清和肝内变化通过qRT-PCR和免疫组织化学测定和比较，以未经处理的小鼠。
结果

治疗4周后，平均减少病毒血症是更大的恩替卡韦（带或不带PegIFNα ）治疗比用PegIFNα小鼠。与此相反，循环的HBeAg ，乙肝表面抗原，和肝内的HBcAg的水平显著降低（p值= 0.03）只在单独接受PegIFNα小鼠或组合相比，接受ETV单药治疗的小鼠。渐进抗原减少也证明在接收PegIFNα 12周小鼠（大三阳= Δ1日志;乙肝表面抗原= Δ1.4登录，P < 0.0001 ） 。值得注意的是，时间越长活性PegIFNα的重复给药可能违反HBV感染肝细胞的反应减值及诱导人干扰素刺激基因（ ISG）的持续增强。
结论

PegIFNα的抗病毒效果施加在人肝细胞可诱导持续的反应，并引发大量的HBV抗原下降而不声称的免疫细胞应答的参与。
关键词

    cccDNA的;
    乙肝表面抗原;
    大三阳;
    干扰素刺激基因;
    肝细胞的反应;
    人源化的小鼠

通讯作者联系信息
    通讯作者。地址：内科一处，中心内科，大学医学中心汉堡Eppendorf ， Martinistr 。 52 ，D- 20246德国汉堡。电话：+49 40 7410 5294 9 ，传真：+49 40 7410 5723 2 。

†

    现在地址： Gilead Sciences公司，福斯特城，加利福尼亚，美国。

版权所有© 2013欧洲肝脏研究协会的研究。发布时间由Elsevier爱尔兰有限公司保留所有权利。