Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis
Background & Aims The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify...
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| Veröffentlicht in: | Journal of hepatology 2012-06, Vol.56 (6), p.1239-1246 |
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| creator | Penna, Amalia Laccabue, Diletta Libri, Irene Giuberti, Tiziana Schivazappa, Simona Alfieri, Arianna Mori, Cristina Canetti, Diana Lampertico, Pietro Viganò, Mauro Colombo, Massimo Loggi, Elisabetta Missale, Gabriele Ferrari, Carlo |
| description | Background & Aims The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. Methods HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. Results Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA |
| doi_str_mv | 10.1016/j.jhep.2011.12.032 |
| format | Article |
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Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. Methods HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. Results Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. Conclusions IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.</description><identifier>ISSN: 0168-8278</identifier><identifier>EISSN: 1600-0641</identifier><identifier>DOI: 10.1016/j.jhep.2011.12.032</identifier><identifier>PMID: 22326467</identifier><identifier>CODEN: JOHEEC</identifier><language>eng</language><publisher>Kidlington: Elsevier B.V</publisher><subject>Adaptive immunity ; Adult ; Aged ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - therapeutic use ; Antiviral therapy ; Biological and medical sciences ; Cytokines ; Cytokines - biosynthesis ; Female ; Gastroenterology and Hepatology ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatitis B e Antigens - blood ; Hepatitis B Surface Antigens - blood ; Hepatitis B virus - immunology ; Hepatitis B, Chronic - drug therapy ; Hepatitis B, Chronic - immunology ; Humans ; Interferon-alpha - therapeutic use ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Lymphocyte Activation ; Male ; Medical sciences ; Middle Aged ; Other diseases. Semiology ; PD-1 ; Pharmacology. Drug treatments ; Polyethylene Glycols - therapeutic use ; Recombinant Proteins - therapeutic use ; T-Lymphocytes - immunology</subject><ispartof>Journal of hepatology, 2012-06, Vol.56 (6), p.1239-1246</ispartof><rights>European Association for the Study of the Liver</rights><rights>2012 European Association for the Study of the Liver</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-a5dba7f3e5b47d0da895debfe4be66453492d471c57c44d81eb636dbaf7b18953</citedby><cites>FETCH-LOGICAL-c441t-a5dba7f3e5b47d0da895debfe4be66453492d471c57c44d81eb636dbaf7b18953</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jhep.2011.12.032$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>315,781,785,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25884117$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22326467$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Penna, Amalia</creatorcontrib><creatorcontrib>Laccabue, Diletta</creatorcontrib><creatorcontrib>Libri, Irene</creatorcontrib><creatorcontrib>Giuberti, Tiziana</creatorcontrib><creatorcontrib>Schivazappa, Simona</creatorcontrib><creatorcontrib>Alfieri, Arianna</creatorcontrib><creatorcontrib>Mori, Cristina</creatorcontrib><creatorcontrib>Canetti, Diana</creatorcontrib><creatorcontrib>Lampertico, Pietro</creatorcontrib><creatorcontrib>Viganò, Mauro</creatorcontrib><creatorcontrib>Colombo, Massimo</creatorcontrib><creatorcontrib>Loggi, Elisabetta</creatorcontrib><creatorcontrib>Missale, Gabriele</creatorcontrib><creatorcontrib>Ferrari, Carlo</creatorcontrib><title>Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis</title><title>Journal of hepatology</title><addtitle>J Hepatol</addtitle><description>Background & Aims The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. Methods HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. Results Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. Conclusions IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.</description><subject>Adaptive immunity</subject><subject>Adult</subject><subject>Aged</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - therapeutic use</subject><subject>Antiviral therapy</subject><subject>Biological and medical sciences</subject><subject>Cytokines</subject><subject>Cytokines - biosynthesis</subject><subject>Female</subject><subject>Gastroenterology and Hepatology</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatitis B e Antigens - blood</subject><subject>Hepatitis B Surface Antigens - blood</subject><subject>Hepatitis B virus - immunology</subject><subject>Hepatitis B, Chronic - drug therapy</subject><subject>Hepatitis B, Chronic - immunology</subject><subject>Humans</subject><subject>Interferon-alpha - therapeutic use</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Lymphocyte Activation</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Other diseases. Semiology</subject><subject>PD-1</subject><subject>Pharmacology. Drug treatments</subject><subject>Polyethylene Glycols - therapeutic use</subject><subject>Recombinant Proteins - therapeutic use</subject><subject>T-Lymphocytes - immunology</subject><issn>0168-8278</issn><issn>1600-0641</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9ktGK1DAUhoO4uOPqC3ghvRG8aU3SNG1BhHVRV1hQcPU2pMnpTGon6SadhfGtfJF9Jk-Z0QUv9ioQvv_Pycch5AWjBaNMvhmKYQNTwSljBeMFLfkjsmKS0pxKwR6TFUJN3vC6OSVPUxoopSVtxRNyynnJpZD1ivz6CmvnZ4g9xODzu9-ZDZAyH-bMbacYbiEDHcd9NkF00waiHrNuDMFml-9_5GkC43pnsuvcwDhmEdIUfMIC5xGA83XuYa1nhzVmgw8giiPjxezSM3LS6zHB8-N5Rr5__HB9cZlfffn0-eL8KjdCsDnXle103ZdQdaK21OqmrSx0PYgOpBRVKVpuRc1MVWPANgw6WUrM9HXHkC3PyOtDL37nZgdpVluXlnG1h7BLCl1WXMhWlojyA2piSClCr6botjruEVo4qQa1OFeLc8W4QucYenns33VbsP8ifyUj8OoI6GT02EftjUv3XNU0grGFe3vgAG3cOogqGQfegHURzKxscA_P8e6_uBkdGtfjT9hDGsIuevSsmEoYUN-W7ViWg3GKLbQt_wAKTLbO</recordid><startdate>20120601</startdate><enddate>20120601</enddate><creator>Penna, Amalia</creator><creator>Laccabue, Diletta</creator><creator>Libri, Irene</creator><creator>Giuberti, Tiziana</creator><creator>Schivazappa, Simona</creator><creator>Alfieri, Arianna</creator><creator>Mori, Cristina</creator><creator>Canetti, Diana</creator><creator>Lampertico, Pietro</creator><creator>Viganò, Mauro</creator><creator>Colombo, Massimo</creator><creator>Loggi, Elisabetta</creator><creator>Missale, Gabriele</creator><creator>Ferrari, Carlo</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20120601</creationdate><title>Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis</title><author>Penna, Amalia ; Laccabue, Diletta ; Libri, Irene ; Giuberti, Tiziana ; Schivazappa, Simona ; Alfieri, Arianna ; Mori, Cristina ; Canetti, Diana ; Lampertico, Pietro ; Viganò, Mauro ; Colombo, Massimo ; Loggi, Elisabetta ; Missale, Gabriele ; Ferrari, Carlo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-a5dba7f3e5b47d0da895debfe4be66453492d471c57c44d81eb636dbaf7b18953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptive immunity</topic><topic>Adult</topic><topic>Aged</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - therapeutic use</topic><topic>Antiviral therapy</topic><topic>Biological and medical sciences</topic><topic>Cytokines</topic><topic>Cytokines - biosynthesis</topic><topic>Female</topic><topic>Gastroenterology and Hepatology</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Hepatitis B e Antigens - blood</topic><topic>Hepatitis B Surface Antigens - blood</topic><topic>Hepatitis B virus - immunology</topic><topic>Hepatitis B, Chronic - drug therapy</topic><topic>Hepatitis B, Chronic - immunology</topic><topic>Humans</topic><topic>Interferon-alpha - therapeutic use</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Lymphocyte Activation</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Other diseases. Semiology</topic><topic>PD-1</topic><topic>Pharmacology. Drug treatments</topic><topic>Polyethylene Glycols - therapeutic use</topic><topic>Recombinant Proteins - therapeutic use</topic><topic>T-Lymphocytes - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Penna, Amalia</creatorcontrib><creatorcontrib>Laccabue, Diletta</creatorcontrib><creatorcontrib>Libri, Irene</creatorcontrib><creatorcontrib>Giuberti, Tiziana</creatorcontrib><creatorcontrib>Schivazappa, Simona</creatorcontrib><creatorcontrib>Alfieri, Arianna</creatorcontrib><creatorcontrib>Mori, Cristina</creatorcontrib><creatorcontrib>Canetti, Diana</creatorcontrib><creatorcontrib>Lampertico, Pietro</creatorcontrib><creatorcontrib>Viganò, Mauro</creatorcontrib><creatorcontrib>Colombo, Massimo</creatorcontrib><creatorcontrib>Loggi, Elisabetta</creatorcontrib><creatorcontrib>Missale, Gabriele</creatorcontrib><creatorcontrib>Ferrari, Carlo</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of hepatology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Penna, Amalia</au><au>Laccabue, Diletta</au><au>Libri, Irene</au><au>Giuberti, Tiziana</au><au>Schivazappa, Simona</au><au>Alfieri, Arianna</au><au>Mori, Cristina</au><au>Canetti, Diana</au><au>Lampertico, Pietro</au><au>Viganò, Mauro</au><au>Colombo, Massimo</au><au>Loggi, Elisabetta</au><au>Missale, Gabriele</au><au>Ferrari, Carlo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis</atitle><jtitle>Journal of hepatology</jtitle><addtitle>J Hepatol</addtitle><date>2012-06-01</date><risdate>2012</risdate><volume>56</volume><issue>6</issue><spage>1239</spage><epage>1246</epage><pages>1239-1246</pages><issn>0168-8278</issn><eissn>1600-0641</eissn><coden>JOHEEC</coden><abstract>Background & Aims The effect of IFN-α therapy on HBV-specific T-cell responses in HBeAg-negative, genotype D, chronic hepatitis B is largely undefined. Understanding to what extent IFN-α can modulate HBV-specific T-cells is important to define strategies to optimize IFN efficacy and to identify immunological parameters to predict response to therapy. Methods HBV-specific T-cell responses were analyzed longitudinally ex vivo and after expansion in vitro in 15 patients with genotype D, HBeAg-negative chronic hepatitis B treated with peginterferon-α-2a. HBV proteins and synthetic peptides were used to stimulate T-cell responses. Analysis of the CD4 and CD8 T-cell functions was performed by ELISPOT, intracellular cytokine and tetramer staining. The effect of anti-PD-L1 on T-cell functions was also analyzed. Results Ex vivo IFN-γ production by total HBV-specific T-cells was significantly greater before therapy in patients who showed HBV DNA <50 IU/ml at weeks 24 and/or 48 of therapy. No significant improvement of T-cell proliferation, Th1 cytokine production and cytotoxicity was observed during IFN therapy by both ex vivo and in vitro analysis. PD-1/PD-L1 blockade showed a modest improvement of cytokine production in a total of 15% of T-cell lines. Conclusions IFN-α did not improve peripheral blood HBV-specific T-cell responses in the first 24 weeks of treatment, consistent either with a predominant antiviral/antiproliferative effect or with an immunomodulatory activity on other arms of the immune system which were not analyzed in our study. A better pre-treatment ex vivo IFN-γ production was associated with better chances to control HBV replication during therapy and represents a promising predictor of IFN efficacy.</abstract><cop>Kidlington</cop><pub>Elsevier B.V</pub><pmid>22326467</pmid><doi>10.1016/j.jhep.2011.12.032</doi><tpages>8</tpages></addata></record> |
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| subjects | Adaptive immunity Adult Aged Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - therapeutic use Antiviral therapy Biological and medical sciences Cytokines Cytokines - biosynthesis Female Gastroenterology and Hepatology Gastroenterology. Liver. Pancreas. Abdomen Hepatitis B e Antigens - blood Hepatitis B Surface Antigens - blood Hepatitis B virus - immunology Hepatitis B, Chronic - drug therapy Hepatitis B, Chronic - immunology Humans Interferon-alpha - therapeutic use Liver. Biliary tract. Portal circulation. Exocrine pancreas Lymphocyte Activation Male Medical sciences Middle Aged Other diseases. Semiology PD-1 Pharmacology. Drug treatments Polyethylene Glycols - therapeutic use Recombinant Proteins - therapeutic use T-Lymphocytes - immunology |
| title | Peginterferon-α does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis |
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