Document Detail

Alcohol dehydrogenase-specific T-cell responses are associated with alcohol consumption in patients with alcohol-related cirrhosis.
MedLine Citation:
PMID:  23424168     Owner:  NLM     Status:  MEDLINE    
Patients with alcohol-related liver disease (ALD) have antibodies directed to alcohol dehydrogenase (ADH), anti-ADH titers being associated with disease severity and active alcohol consumption. ADH-specific T-cell responses have not been characterized. We aimed to define anti-ADH cellular immune responses and their association with active alcohol consumption and disease severity. Using cultures of peripheral blood mononuclear cells (PBMCs) from 25 patients with alcohol-related cirrhosis (ARC; 12 were actively drinking or abstinent for <6 months, and 13 were abstinent for >6 months) and hepatic mononuclear cells (HMCs) from 14 patients with ARC who were undergoing transplantation, we investigated T-cell reactivity to 25 overlapping peptides representing the full human ADH protein (beta 1 subunit). ADH-specific peripheral T-cell responses were assessed by the quantification of T-cell proliferation and cytokine production and were correlated with the clinical course. In active alcohol consumers, proliferative T-cell responses targeted ADH31-95 and other discontinuous sequences in the ADH peptide, whereas only one sequence was targeted in abstinents. ADH peptides induced the production of interferon-γ (IFN-γ), interleukin-4 (IL-4), and IL-17. IL-4 production was lower in active drinkers versus abstinents, and IL-17 production was higher. Peptides inducing IFN-γ production outnumbered those inducing T-cell proliferation. The intensity of the predominantly T helper 1 (Th 1) responses directly correlated with disease severity. Similar to PBMCs in abstinents, ADH peptides induced weak T-cell proliferation and a similar level of IL-4 production in HMCs but less vigorous Th 1 and T helper 17 responses. Conclusion: This suggests that Th 1 responses to ADH in ARC are induced by alcohol consumption. A Th 1/T helper 2 imbalance characterizes T-cell responses in active drinkers with ARC, whereas IL-4 production prevails in abstinents. This identifies new targets for immunoregulatory therapies in ALD patients for halting detrimental effector T-cell responses, which may encourage liver fibrogenesis and progression to end-stage liver disease.
Fang Lin; Nicholas J Taylor; Haibin Su; Xiaohong Huang; Munther J Hussain; Robin Daniel Abeles; Laura Blackmore; Yunyun Zhou; Mohammad Mashfick Ikbal; Nigel Heaton; Wayel Jassem; Debbie L Shawcross; Diego Vergani; Yun Ma
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-05-27
Journal Detail:
Title:  Hepatology (Baltimore, Md.)     Volume:  58     ISSN:  1527-3350     ISO Abbreviation:  Hepatology     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-26     Completed Date:  2013-08-30     Revised Date:  2014-03-14    
Medline Journal Info:
Nlm Unique ID:  8302946     Medline TA:  Hepatology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  314-24     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Association for the Study of Liver Diseases.
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MeSH Terms
Alcohol Dehydrogenase / immunology*
Alcohol Drinking / immunology*
Interferon-gamma / biosynthesis
Interleukin-17 / biosynthesis
Interleukin-4 / biosynthesis
Leukocytes, Mononuclear / metabolism
Liver Cirrhosis, Alcoholic / immunology*
Middle Aged
Peptide Fragments / immunology,  pharmacology
T-Lymphocytes / immunology*
Th1 Cells / immunology
Grant Support
DRF-2009-02-01//Department of Health; MR/J006742/1//Medical Research Council
Reg. No./Substance:
0/Interleukin-17; 0/Peptide Fragments; 207137-56-2/Interleukin-4; 82115-62-6/Interferon-gamma; EC Dehydrogenase
Comment In:
Nat Rev Gastroenterol Hepatol. 2013 Apr;10(4):196   [PMID:  23478388 ]

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