强化免疫活动的肝内转录签名预测响应聚乙二醇干扰素治疗

StephenW

Original Article
An intrahepatic transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B

    Louis Jansen1,2,
    Annikki de Niet1,2,
    Zuzanna Makowska3,
    Michael T. Dill3,
    Karel A. van Dort2,
    Valeska Terpstra4,
    R. Bart Takkenberg1,
    Harry L.A. Janssen5,6,
    Markus H. Heim3,
    Neeltje A. Kootstra2 and
    Hendrik W. Reesink1,2,*

DOI: 10.1111/liv.12768

This article is protected by copyright. All rights reserved.

Issue
Vol. 35 Issue
Liver International

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)


Author Information

    1    Department of Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, the Netherlands
    2    Department of Experimental Immunology, AMC, UvA, the Netherlands
    3    Department of Biomedicine, University of Basel, Basel, Switzerland
    4    Department of Pathology, Bronovo Hospital, The Hague, the Netherlands
    5    Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
    6    Liver Clinic, Toronto Western and General Hospital University Health Network, Toronto, Canada

* Contact information corresponding author
H.W. Reesink
Department of Gastroenterology and Hepatology
Academic Medical Center, University of Amsterdam
Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Phone: +31 20 56 68 728 Fax: +31 20 56 69 582
E-mail: [email protected]

    This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/liv.12768


Abstract
Background

Differences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B (CHB) patients.

Methods

We employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48 weeks, and compared expression patterns of combined responders (HBeAg loss, HBV-DNA <2,000 IU/mL, alanine aminotransferase normalization after one year of treatment-free follow-up) with non-responders. Genes identified by transcriptome analysis in 15 biopsies were confirmed in 25 additional biopsies by RT-qPCR.

Results

Transcriptome analysis demonstrated significant differences in expression of 41 genes between responders and non-responders. In responders, pathway analysis showed specific upregulation of genes related to the immune response, including chemotaxis and antigen processing and presentation. Genes upregulated in responders exhibited strongest similarity with a set of genes induced in livers of chimpanzees with acute Hepatitis B infection. Differential expression was confirmed for 8 selected genes. A 2-gene subset (HLA-DPB1, SERPIN-E1) was found to predict response most accurately. Incorporation of these genes in a multivariable model with HBeAg status, HBV genotype, and baseline HBsAg level correctly classified 90% of all patients, in which HLA-DPB1 and SERPIN-E1 were independent predictors of response.

Conclusion

We identified an intrahepatic transcriptional signature associated with enhanced immune activation which predicts therapy response. These novel associations could lead to better understanding of responsiveness to peginterferon in CHB patients, and may assist in selecting possible responders to interferon-based treatment.

This article is protected by copyright. All rights reserved.

StephenW

强化免疫活动的肝内转录签名预测响应聚乙二醇干扰素治疗慢性乙型肝炎

    路易斯Jansen1,2，
    Annikki德Niet1,2，
    Zuzanna Makowska3，
    迈克尔·T. Dill3，
    A.卡雷尔面包车Dort2，
    Valeska Terpstra4，
    R.巴特Takkenberg1，
    哈利洛杉矶Janssen5,6，
    马库斯·H. Heim3，
    Neeltje A. Kootstra2和
    亨德里克W. Reesink1,2，*

DOI：10.1111/ liv.12768

这篇文章是受版权保护的。版权所有。

问题
第一卷。 35问题
肝国际

接受第（接受，未经编辑的文章在网上和引述的公布，最终编辑和记录排版本将出现在未来。）


作者信息

    胃肠病学和肝病，学术医学中心（AMC），阿姆斯特丹大学（UVA），阿姆斯特丹，荷兰1系
    实验免疫学，AMC，阿姆斯特丹，荷兰2部
    生物医药，巴塞尔大学，瑞士巴塞尔3系
    病理，Bronovo医院，海牙，荷兰4部
    胃肠病学和肝病，伊拉兹马斯MC，大学医学中心鹿特丹，荷兰鹿特丹的5系
    6肝门诊，多伦多西部和综合医院大学健康网络多伦多，加拿大

*通讯作者联系方式
H.W。 Reesink
胃肠病学和肝病科
学术医学中心，阿姆斯特丹大学
Meibergdreef9，1105 AZ阿姆斯特丹，荷兰
电话：+31205668728传真：+31205669582
电子邮件：[email protected]

    这篇文章已被接受发表，并接受全面的同行评审，但经过审稿，排版，分页和校对过程中，这可能会导致这个版本和记录的版本之间的差异一直没有。请引用这篇文章的DOI：10.1111/ liv.12768


抽象
背景

在肝内的基因表达模式的差异可能与聚乙二醇干扰素治疗慢性乙型肝炎（CHB）的患者的治疗的响应相关联。

方法：

我们采用基因表达谱的40例慢性乙型肝炎患者的基线肝活检（19例HBeAg阳性;21例HBeAg阴性）与聚乙二醇干扰素和阿德福韦治疗48周，比较结合反应的表达模式（HBeAg转阴，HBV-DNA<2000 IU /毫升，一年无治疗随访后丙氨酸转氨酶正常化）与非反应者。在15活检确定转录组分析基因25个活检通过RT-qPCR的证实。

结果

转录组分析证明的应答者和非应答者之间的41个基因的表达显著差异。在反应者，通路分析显示相关的免疫反应，包括趋化性和抗原加工和呈递的基因特异性上调。基因上调反应表现最强的相似性与一组诱导黑猩猩急性乙肝感染的肝脏基因。差异表达证实为8选择的基因。一个2基因的子集（HLA-DPB1，丝氨酸蛋白酶抑制剂-E1）被发现最准确地预测响应。结合这些基因与HBeAg状态，HBV基因型，基线的HBsAg水平多变量模型的正确分类90％的患者，其中HLA-DPB1和丝氨酸蛋白酶抑制剂-E1是反应的独立预测因子的。

结论

我们确定了具有增强免疫激活它预测治疗反应相关的转录肝内签名。这些新的社团可能会导致更好地理解反应聚乙二醇干扰素慢性乙型肝炎患者，并可能帮助选择可能的反应，以干扰素为基础的治疗。

这篇文章是受版权保护的。版权所有。