*These authors contributed equally to this work.
Liver Failure/Cirrhosis/Portal Hypertension
Article first published online: 27 MAY 2013
Copyright © 2013 American Association for the Study of Liver Diseases
Volume 58, Issue 1, pages 314–324, July 2013
How to Cite
Lin, F., Taylor, N. J., Su, H., Huang, X., Hussain, M. J., Abeles, R. D., Blackmore, L., Zhou, Y., Ikbal, M. M., Heaton, N., Jassem, W., Shawcross, D. L., Vergani, D. and Ma, Y. (2013), Alcohol dehydrogenase–specific T-cell responses are associated with alcohol consumption in patients with alcohol-related cirrhosis. Hepatology, 58: 314–324. doi: 10.1002/hep.26334
Potential conflict of interest: Nothing to report.
Fang Lin and Haibin Su were supported by scholarships from Beijing 302 Hospital, Robin Daniel Abeles was supported by a clinician training fellowship from the National Institute for Health Research, and Debbie L. Shawcross was supported by a 5-year clinical senior lectureship from the Higher Education Funding Council for England.
- Issue published online: 24 JUN 2013
- Article first published online: 27 MAY 2013
- Accepted manuscript online: 19 FEB 2013 10:26AM EST
- Manuscript Accepted: 1 FEB 2013
- Manuscript Received: 5 OCT 2012
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 (Th1) 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 Th1 and T helper 17 responses. Conclusion: This suggests that Th1 responses to ADH in ARC are induced by alcohol consumption. A Th1/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. (HEPATOLOGY 2013)