Alcohol dehydrogenase-specific T-cell responses are associated with alcohol consumption in patients with alcohol-related cirrhosis
| Autor: | N.J. Taylor, Yunyun Zhou, Mohammad Mashfick Ikbal, Debbie L. Shawcross, Robin Daniel Abeles, Wayel Jassem, Diego Vergani, Haibin Su, Nigel Heaton, Yun Ma, Laura Blackmore Blackmore, Munther Hussain, X. Huang, Fang Lin |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Adult
Male Cirrhosis Alcohol Drinking T-Lymphocytes Temperance T cell Biology Peripheral blood mononuclear cell Interferon-gamma Liver disease Immune system Antigen Liver Cirrhosis Alcoholic medicine Humans Aged Alcohol dehydrogenase Hepatology Interleukin-17 Alcohol Dehydrogenase Middle Aged Th1 Cells medicine.disease Peptide Fragments Transplantation medicine.anatomical_structure Immunology Leukocytes Mononuclear biology.protein Female Interleukin-4 |
| Zdroj: | Hepatology. 58:314-324 |
| ISSN: | 0270-9139 |
| Popis: | 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 for6 months, and 13 were abstinent for6 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.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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text