title: Alcohol dehydrogenase-specific T-cell responses are associated with alcohol consumption in patients with alcohol-related cirrhosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Institute of Liver Studies, School of Medicine at King's College Hospital, King's College London, London, United Kingdom.
authors: Fang
authors: F
authors: Lin
authors: Nicholas J
authors: NJ
authors: Taylor
authors: Haibin
authors: H
authors: Su
authors: Xiaohong
authors: X
authors: Huang
authors: Munther J
authors: MJ
authors: Hussain
authors: Robin Daniel
authors: RD
authors: Abeles
authors: Laura
authors: L
authors: Blackmore
authors: Yunyun
authors: Y
authors: Zhou
authors: Mohammad Mashfick
authors: MM
authors: Ikbal
authors: Nigel
authors: N
authors: Heaton
authors: Wayel
authors: W
authors: Jassem
authors: Debbie L
authors: DL
authors: Shawcross
authors: Diego
authors: D
authors: Vergani
authors: Yun
authors: Y
authors: Ma
mesh_terms: D000328:Adult; D000368:Aged; D000426:Alcohol Dehydrogenase / Q000276:immunology*; D000428:Alcohol Drinking / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D013695:Temperance; D018417:Th1 Cells / Q000276:immunology
chemical_list: D020381:Interleukin-17; D010446:Peptide Fragments; D015847:Interleukin-4; D007371:Interferon-gamma; D000426:Alcohol Dehydrogenase