Alcohol Dehydrogenase-Specific T-Cell Responses Are Associated With Alcohol Consumption in Patients With Alcohol-Related Cirrhosis
Alcohol Dehydrogenase-Specific T-Cell Responses Are Associated With Alcohol Consumption in Patients With Alcohol-Related Cirrhosis
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DOI：
10.1002/hep.26334
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发表时间：
2013-07-01
期刊：
影响因子：
13.5
通讯作者：
Ma, Yun
中科院分区：
文献类型：
--
作者：
Lin, Fang;Taylor, Nicholas J.;Ma, Yun
酒精相关性肝病（ALD）患者有针对酒精脱氢酶（ADH）的抗体，抗ADH滴度与疾病严重程度和主动饮酒有关。adh特异性t细胞反应尚未被描述。我们的目的是确定抗adh细胞免疫反应及其与主动饮酒和疾病严重程度的关系。利用25例酒精相关性肝硬化患者（ARC，其中12例积极饮酒或戒酒< 6个月，13例戒酒≤6个月）的外周血单个核细胞（PBMCs）和14例接受移植的ARC患者的肝单个核细胞（HMCs）的培养，我们研究了t细胞对25种重叠肽的反应性，这些肽代表了完整的人ADH蛋白（β 1亚基）。通过量化t细胞增殖和细胞因子产生来评估adh特异性外周t细胞反应，并与临床病程相关。在活跃的酒精饮用者中，增殖性t细胞反应针对ADH31-95和ADH肽中的其他不连续序列，而在戒酒者中只有一个序列被靶向。ADH肽诱导干扰素- γ (ifn - γ)、白细胞介素-4 （IL-4）和IL-17的产生。与不饮酒者相比，积极饮酒者IL-4的产生较低，而IL-17的产生较高。诱导ifn - γ产生的多肽多于诱导t细胞增殖的多肽。主要的T辅助1 （T(h)1）反应的强度与疾病严重程度直接相关。与戒断的PBMCs类似，ADH肽诱导HMCs的T细胞增殖弱，IL-4产生水平相似，但T(h)1和T辅助17反应较弱。结论：这表明酒精可诱导ARC中T(h)1对ADH的反应。A T(h)1/辅助性T 2失衡是ARC活跃饮酒者T细胞反应的特征，而IL-4产生在戒酒者中普遍存在。这为ALD患者的免疫调节治疗确定了新的靶点，以阻止有害效应t细胞反应，这可能会促进肝纤维化和进展到终末期肝病。
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-gamma (IFN-gamma), 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-gamma production outnumbered those inducing T-cell proliferation. The intensity of the predominantly T helper 1 (T(h)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 T(h)1 and T helper 17 responses. Conclusion: This suggests that T(h)1 responses to ADH in ARC are induced by alcohol consumption. A T(h)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.