Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis

Hepatitis C virus (HCV)‐specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV‐specific CD8+ T cells, is a key regulatory cytokine modulating HCV‐specific effector T cells. Here we s...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Md.), 2012-12, Vol.56 (6), p.2094-2105
Hauptverfasser: Li, Shaoyong, Vriend, Lianne E.M., Nasser, Imad A., Popov, Yury, Afdhal, Nezam H., Koziel, Margaret J., Schuppan, Detlef, Exley, Mark A., Alatrakchi, Nadia
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container_end_page 2105
container_issue 6
container_start_page 2094
container_title Hepatology (Baltimore, Md.)
container_volume 56
creator Li, Shaoyong
Vriend, Lianne E.M.
Nasser, Imad A.
Popov, Yury
Afdhal, Nezam H.
Koziel, Margaret J.
Schuppan, Detlef
Exley, Mark A.
Alatrakchi, Nadia
description Hepatitis C virus (HCV)‐specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV‐specific CD8+ T cells, is a key regulatory cytokine modulating HCV‐specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV‐specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross‐sectional study of two well‐defined groups of HCV‐infected subjects with slow (≤0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV‐specific T‐cell responses were studied using interferon‐gamma (IFNγ)‐ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme‐linked immunosorbent assay (ELISA) and multiparameter fluorescence‐activated cell sorting (FACS). The effects of IHL stimulated with HCV‐core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV‐specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV‐specific IFNγ responses strongly correlated with HCV‐specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV‐specific IL‐10. HCV‐specific TGFβ was produced by CD8 and CD4 T cells. HCV‐specific TGFβ, not interleukin (IL)‐10, inversely correlated with liver inflammation (R = −0.63, P = 0.008) and, unexpectedly, fibrosis (R = −0.46, P = 0.05). In addition, supernatants from HCV‐stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti‐TGFβ mAb abrogated such expression. Conclusion: Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV‐specific T cells appeared to have a protective role in HCV‐infected liver, together with other T‐cell‐derived factors, ameliorating HCV liver disease progression. (HEPATOLOGY 2012;56:2094–2105)
doi_str_mv 10.1002/hep.25951
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Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV‐specific CD8+ T cells, is a key regulatory cytokine modulating HCV‐specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV‐specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross‐sectional study of two well‐defined groups of HCV‐infected subjects with slow (≤0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV‐specific T‐cell responses were studied using interferon‐gamma (IFNγ)‐ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme‐linked immunosorbent assay (ELISA) and multiparameter fluorescence‐activated cell sorting (FACS). The effects of IHL stimulated with HCV‐core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV‐specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV‐specific IFNγ responses strongly correlated with HCV‐specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV‐specific IL‐10. HCV‐specific TGFβ was produced by CD8 and CD4 T cells. HCV‐specific TGFβ, not interleukin (IL)‐10, inversely correlated with liver inflammation (R = −0.63, P = 0.008) and, unexpectedly, fibrosis (R = −0.46, P = 0.05). In addition, supernatants from HCV‐stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti‐TGFβ mAb abrogated such expression. Conclusion: Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV‐specific T cells appeared to have a protective role in HCV‐infected liver, together with other T‐cell‐derived factors, ameliorating HCV liver disease progression. (HEPATOLOGY 2012;56:2094–2105)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.25951</identifier><identifier>PMID: 22806830</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adult ; Aged ; Biological and medical sciences ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Collagen Type I - genetics ; Cross-Sectional Studies ; Cytokines ; Disease Progression ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression ; Hepacivirus - immunology ; Hepatic Stellate Cells - metabolism ; Hepatitis ; Hepatitis C ; Hepatitis C, Chronic - immunology ; Hepatitis C, Chronic - metabolism ; Hepatitis C, Chronic - pathology ; Hepatology ; Humans ; Interferon-gamma - metabolism ; Interleukin-10 - metabolism ; Liver - immunology ; Liver - metabolism ; Liver cirrhosis ; Liver Cirrhosis - immunology ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - pathology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Lymphocytes ; Male ; Matrix Metalloproteinase 1 - genetics ; Medical sciences ; Middle Aged ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism ; Transforming Growth Factor beta - metabolism ; Viral Core Proteins - immunology</subject><ispartof>Hepatology (Baltimore, Md.), 2012-12, Vol.56 (6), p.2094-2105</ispartof><rights>Copyright © 2012 American Association for the Study of Liver Diseases</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4771-6e720ca9a46de1f46487413da073b0fdd087482a0bc4fc47e6051f5e9ead6c983</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.25951$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.25951$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=26853020$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22806830$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Shaoyong</creatorcontrib><creatorcontrib>Vriend, Lianne E.M.</creatorcontrib><creatorcontrib>Nasser, Imad A.</creatorcontrib><creatorcontrib>Popov, Yury</creatorcontrib><creatorcontrib>Afdhal, Nezam H.</creatorcontrib><creatorcontrib>Koziel, Margaret J.</creatorcontrib><creatorcontrib>Schuppan, Detlef</creatorcontrib><creatorcontrib>Exley, Mark A.</creatorcontrib><creatorcontrib>Alatrakchi, Nadia</creatorcontrib><title>Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Hepatitis C virus (HCV)‐specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV‐specific CD8+ T cells, is a key regulatory cytokine modulating HCV‐specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV‐specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross‐sectional study of two well‐defined groups of HCV‐infected subjects with slow (≤0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV‐specific T‐cell responses were studied using interferon‐gamma (IFNγ)‐ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme‐linked immunosorbent assay (ELISA) and multiparameter fluorescence‐activated cell sorting (FACS). The effects of IHL stimulated with HCV‐core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV‐specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV‐specific IFNγ responses strongly correlated with HCV‐specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV‐specific IL‐10. HCV‐specific TGFβ was produced by CD8 and CD4 T cells. HCV‐specific TGFβ, not interleukin (IL)‐10, inversely correlated with liver inflammation (R = −0.63, P = 0.008) and, unexpectedly, fibrosis (R = −0.46, P = 0.05). In addition, supernatants from HCV‐stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti‐TGFβ mAb abrogated such expression. Conclusion: Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV‐specific T cells appeared to have a protective role in HCV‐infected liver, together with other T‐cell‐derived factors, ameliorating HCV liver disease progression. (HEPATOLOGY 2012;56:2094–2105)</description><subject>Adult</subject><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Collagen Type I - genetics</subject><subject>Cross-Sectional Studies</subject><subject>Cytokines</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression</subject><subject>Hepacivirus - immunology</subject><subject>Hepatic Stellate Cells - metabolism</subject><subject>Hepatitis</subject><subject>Hepatitis C</subject><subject>Hepatitis C, Chronic - immunology</subject><subject>Hepatitis C, Chronic - metabolism</subject><subject>Hepatitis C, Chronic - pathology</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin-10 - metabolism</subject><subject>Liver - immunology</subject><subject>Liver - metabolism</subject><subject>Liver cirrhosis</subject><subject>Liver Cirrhosis - immunology</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - pathology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Lymphocytes</subject><subject>Male</subject><subject>Matrix Metalloproteinase 1 - genetics</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Viral Core Proteins - immunology</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkkuP0zAUhS0EYsrAgj-ALCEkNpnxI3aSDRIaDS1SNSAeYmk5znXrIY2DnbQz_36ctpTHyrbud47vPTZCLym5oISwyzX0F0xUgj5CMypYkXEuyGM0I6wgWUV5dYaexXhLCKlyVj5FZ4yVRJaczNB2Ab0e3OAiNnjrwhiz2INx1hk8ZAbaNmsguC00eAi6i9aHjetWeBX8blhjq83gA65h0DhZ6Bi9cXpI9M6lcmz9Dq_3NxhsXR38CjqILj5HT6xuI7w4rufo-4frb1eLbPlp_vHq_TIzeVHQTELBiNGVzmUD1OYyL4uc8kaTgtfENg1J55JpUpvcJglIIqgVUIFupKlKfo7eHXz7sd5AY6BLU7SqD26jw73y2ql_K51bq5XfqhRgSQuRDN4eDYL_NUIc1MbFKRbdgR-joozxnDORy4S-_g-99WPo0ngTRYUUgkyGr_7u6NTK7ydJwJsjoKPRrU2pGxf_cLIUnLCJuzxwO9fC_alOiZr-hEqpq_2fUIvrz_tNUmQHhYsD3J0UOvxUsuCFUD9u5upLJb_OlzdcVfwBv6u6AA</recordid><startdate>201212</startdate><enddate>201212</enddate><creator>Li, Shaoyong</creator><creator>Vriend, Lianne E.M.</creator><creator>Nasser, Imad A.</creator><creator>Popov, Yury</creator><creator>Afdhal, Nezam H.</creator><creator>Koziel, Margaret J.</creator><creator>Schuppan, Detlef</creator><creator>Exley, Mark A.</creator><creator>Alatrakchi, Nadia</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><general>Wolters Kluwer Health, Inc</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201212</creationdate><title>Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis</title><author>Li, Shaoyong ; Vriend, Lianne E.M. ; Nasser, Imad A. ; Popov, Yury ; Afdhal, Nezam H. ; Koziel, Margaret J. ; Schuppan, Detlef ; Exley, Mark A. ; Alatrakchi, Nadia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4771-6e720ca9a46de1f46487413da073b0fdd087482a0bc4fc47e6051f5e9ead6c983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Biological and medical sciences</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>Collagen Type I - genetics</topic><topic>Cross-Sectional Studies</topic><topic>Cytokines</topic><topic>Disease Progression</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression</topic><topic>Hepacivirus - immunology</topic><topic>Hepatic Stellate Cells - metabolism</topic><topic>Hepatitis</topic><topic>Hepatitis C</topic><topic>Hepatitis C, Chronic - immunology</topic><topic>Hepatitis C, Chronic - metabolism</topic><topic>Hepatitis C, Chronic - pathology</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin-10 - metabolism</topic><topic>Liver - immunology</topic><topic>Liver - metabolism</topic><topic>Liver cirrhosis</topic><topic>Liver Cirrhosis - immunology</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Liver Cirrhosis - pathology</topic><topic>Liver. Biliary tract. Portal circulation. 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Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV‐specific CD8+ T cells, is a key regulatory cytokine modulating HCV‐specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV‐specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross‐sectional study of two well‐defined groups of HCV‐infected subjects with slow (≤0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV‐specific T‐cell responses were studied using interferon‐gamma (IFNγ)‐ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme‐linked immunosorbent assay (ELISA) and multiparameter fluorescence‐activated cell sorting (FACS). The effects of IHL stimulated with HCV‐core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV‐specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV‐specific IFNγ responses strongly correlated with HCV‐specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV‐specific IL‐10. HCV‐specific TGFβ was produced by CD8 and CD4 T cells. HCV‐specific TGFβ, not interleukin (IL)‐10, inversely correlated with liver inflammation (R = −0.63, P = 0.008) and, unexpectedly, fibrosis (R = −0.46, P = 0.05). In addition, supernatants from HCV‐stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti‐TGFβ mAb abrogated such expression. Conclusion: Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV‐specific T cells appeared to have a protective role in HCV‐infected liver, together with other T‐cell‐derived factors, ameliorating HCV liver disease progression. (HEPATOLOGY 2012;56:2094–2105)</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>22806830</pmid><doi>10.1002/hep.25951</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Adult
Aged
Biological and medical sciences
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - metabolism
Collagen Type I - genetics
Cross-Sectional Studies
Cytokines
Disease Progression
Female
Gastroenterology. Liver. Pancreas. Abdomen
Gene Expression
Hepacivirus - immunology
Hepatic Stellate Cells - metabolism
Hepatitis
Hepatitis C
Hepatitis C, Chronic - immunology
Hepatitis C, Chronic - metabolism
Hepatitis C, Chronic - pathology
Hepatology
Humans
Interferon-gamma - metabolism
Interleukin-10 - metabolism
Liver - immunology
Liver - metabolism
Liver cirrhosis
Liver Cirrhosis - immunology
Liver Cirrhosis - metabolism
Liver Cirrhosis - pathology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Lymphocytes
Male
Matrix Metalloproteinase 1 - genetics
Medical sciences
Middle Aged
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - metabolism
Transforming Growth Factor beta - metabolism
Viral Core Proteins - immunology
title Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis
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