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

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 andHendrik W. Reesink1,2,*

Article first published online: 21 JAN 2015

DOI: 10.1111/liv.12768

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Issue

Liver International

Volume 35, Issue 7, pages 1824–1832, July 2015



    1    Department of Gastroenterology and Hepatology, Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands
    2    Department of Experimental Immunology, AMC, Amsterdam, 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

* Correspondence
Hendrik W. Reesink, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Tel: +31 20 56 68 728
Fax: +31 20 56 69 582
e-mail: [email protected]

    This study has been presented in part at The Liver Meeting (AASLD) in Washington, DC (November 4, 2013; abstract #135) and The International Liver Congress (EASL) in London, United Kingdom (April 10, 2014; abstract #181).

   

Abstract
Background & Aims

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 <2000 IU/ml, alanine aminotransferase normalization after 1 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 eight 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.

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·Dill3，卡雷尔面包车A. Dort2，Valeska Terpstra4，R.巴特Takkenberg1，哈利LA Janssen5,6，马库斯·H. Heim3，去往Neeltje A. Kootstra2 andHendrikW¯¯ 。Reesink1,2，*

文章首次在线发表：2015年1月21日

DOI：10.1111 / liv.12768

2014年©约翰·威利父子A / S。由John Wiley＆Sons出版有限公司

问题

肝国际

第35卷，第7期，页1824至1832年，2015年7月



    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
亨德里克·W·Reesink，胃肠病学和肝病学术医学中心，阿姆斯特丹大学，Meibergdreef 9，1105 AZ阿姆斯特丹，荷兰系
电话：+31 20 56 68 728
传真：+31 20 56 69 582
电子邮件：[email protected]

    这项研究已呈现部分在肝脏会（AASLD）在华盛顿特区（2013年11月4日;摘要＃135）和国际肝病大会（EASL）在伦敦，英国（2014年4月10日;摘要＃181 ）。

   

抽象
背景与目的

在肝内的基因表达模式的差异可能与聚乙二醇化干扰素治疗慢性乙型肝炎（CHB）的患者治疗的反应相关联。
方法

我们采用基因表达分析中的40 CHB患者基线肝活检（19 HBeAg阳性; 21 HBeAg阴性）与聚乙二醇化干扰素和阿德福韦治疗48周，并比较结合反应的表达模式（HBeAg消失，HBV-DNA <2,000 IU /毫升，1年的无治疗后随访丙氨酸转氨酶正常化）与非应答者。在15活检确定转录组分析基因的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41个基因的表达显著差异。在应答者，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的具体上调。基因上调反应强烈表现出相似的一组诱导黑猩猩急性乙肝感染的肝脏基因。差异表达证实八个选择的基因。一个2基因子集（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基因型和基线的HBsAg水平多变量模型的正确分类90％的患者，在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。