Alcohol dehydrogenase–specific T‐cell responses are associated with alcohol consumption in patients with alcohol‐related cirrhosis123. Issue 1 (27th May 2013) - Lin, Fang
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 (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)