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,*
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.
作者: StephenW 时间: 2015-6-13 15:39
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，*