Immunological Profiles and prognostic outcomes in patients with alcoholic hepatitis

酒精性肝炎患者的免疫学特征和预后结果

• 批准号: 10190739
• 负责人: Suthat Liangpunsakul
• 金额: $ 21.15万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190739
• 关键词: Abstinence; Acute; Adaptive Immune System; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Antibody Affinity; Antibody Response; Applications Grants; Area; B-Lymphocytes; Bacterial Infections; Bacterial Translocation; Binding; Blood Circulation; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Lineage; Cells; Clinical; Complex; Complication; DNA; Data; Defect; Disease; Disease Outcome; Endotoxins; Ethanol; Fibrosis; Funding Opportunities; Goals; Health; Heavy Drinking; Helper-Inducer T-Lymphocyte; Hepatic; Hepatitis B Vaccination; Hepatocyte; Human; IL8 gene; Immune; Immunologic Memory; Immunologics; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Intestinal permeability; Lead; Light; Link; Lipopolysaccharides; Liver diseases; Malignant Neoplasms; Morbidity - disease rate; Natural Immunity; Neutrophilia; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Plasma; Pneumonia; Process; Reaction; Research; Risk Factors; Rodent Model; Role; Secondary to; Series; Severity of illness; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Time; Toll-like receptors; Translational Research; Vaccines; Violence; Virus Diseases; adaptive immune response; adaptive immunity; cell type; chemokine; chronic alcohol ingestion; clinically significant; cytokine; effective therapy; follow-up; immune activation; infection risk; liver injury; longitudinal analysis; macrophage; microbial; monocyte; mortality; neutrophil; new therapeutic target; novel; problem drinker; prognostic; prognostic significance; response; secondary lymphoid organ; survival outcome

Project Summary Alcoholic hepatitis is a leading cause of morbidity and mortality in the US. Despites its complicated pathogenesis, one of the key drivers in the disease process is the alterations in the innate and adaptive immune responses secondary to excessive alcohol use. This application is in response to the funding opportunity “Alcoholic hepatitis clinical and translational network – translational research (RFA-AA-18-003)”. The goal of our application is to better understand the role and mechanism of innate and adaptive immunity in the pathogenesis of alcoholic hepatitis, as this may help us identify novel therapeutic targets to treat this severe form of ALD. Two specific aims are proposed: Aim# 1: Determine the impact and prognostic significance of microbial translocation, immune dysregulation on the disease severity and outcomes in patients with AH. In this aim, we hypothesized that (i) the state of immune dysregulation has the impact on baseline disease severity and long term outcome of patients with AH and (ii) persistent immune activation during the follow up despite abstinence is adversely affected outcomes of patients with AH. We found that ethanol primes peripheral blood mononuclear cells for LPS-induced inflammatory responses. In sub-aim#1.1, we will perform a detail cross sectional/longitudinal analysis on baseline gut permeability, microbial translocation, immune cell activation/inflammation in healthy controls, ED without liver diseases, and those with AH. We also found that plasma IL-8, a potent chemokine for neutrophils, were markedly elevated in patients with AH. The induction of neutrophils leads to hepatic inflammation/injury with the release of mitochrondrial-DNA containing microparticles (MPs) from the hepatocytes; perpetuating neutrophilia and liver injury. In sub-aim#1.2, we will determine the role and clinical significance of IL-8 and mitochrondrial-DNA (mt-DNA) in patients with AH. Aim#2: Determine the mechanism and significance of alteration in follicular helper T cells in patients with AH. Little is known about how alcohol affects the adaptive immune system, despite the increase risk of infections among those with excessive alcohol use. Follicular T helper (TFH) cells are a CD4 T cell lineage uniquely found in the germinal center reaction of secondary lymphoid organs. The specific function of TFH cells is to select B cells in the germinal center that produce high-affinity Abs. Our novel preliminary data showed, for the first time, on the effect of excessive drinking and ALD on circulating TFH (cTFH) cells. In this aim, we hypothesized that excessive alcohol consumption leads to altered cTFH cell differentiation, and that these effects on cTFH cells are augmented and impacted survival outcomes in patients with AH. We will test that (i) AH patients have dysregulation of cTFH cells, (ii) AH patients have T cell-intrinsic or T cell-extrinsic defects that alter cTFH cell differentiation, and, and (iii) AH patients have abnormal B cell responses secondary to dysregulation in cTFH cells. Our results may shed light on the treatment of AH by targeting specific immunological pathways linking to the pathogenesis of AH.

项目摘要 酒精性肝炎是美国发病率和死亡率的主要原因。蔑视它的复杂性 发病机制，疾病过程中的关键驱动因素之一是先天免疫和获得性免疫的改变。 对过度饮酒的继发性反应。这项申请是对融资机会的回应 “酒精性肝炎临床和翻译网络--翻译研究(RFA-AA-18-003)”。目标是 我们的应用是更好地理解先天免疫和获得性免疫在人类免疫中的作用和机制。 酒精性肝炎的发病机制，因为这可能有助于我们找到治疗这种严重肝炎的新的治疗靶点 ALD的形式。提出了两个具体目标：目标1：确定艾滋病的影响和预后意义 微生物易位、免疫失调对急性肝炎患者病情和预后的影响。在……里面 为了达到这个目的，我们假设：(I)免疫失调状态对基线疾病有影响 急性肝炎患者的严重程度和长期预后以及(Ii)随访期间持续的免疫激活 尽管禁欲，UP仍会对AH患者的预后产生不利影响。我们发现乙醇质数 外周血单个核细胞对内毒素诱导的炎症反应。在次级目标#1.1中，我们将执行 基础肠道通透性、微生物易位、免疫细胞的详细横断面/纵向分析 健康对照组、无肝病的ED和AH患者的活化/炎症反应。我们还发现， 急性肝炎患者血浆IL-8明显升高，是一种有效的中性粒细胞趋化因子。归纳法 中性粒细胞导致肝脏炎症/损伤，释放含有线粒体DNA的 来自肝细胞的微粒(MPS)；使中性粒细胞永久化和肝损伤。在分目标1.2中，我们将 探讨IL-8和线粒体DNA(mt-DNA)在急性肝炎患者中的作用及临床意义。 目的#2：探讨慢性粒细胞白血病患者滤泡辅助性T细胞改变的机制及意义 阿。人们对酒精如何影响适应性免疫系统知之甚少，尽管酒精会增加患酒精性心脏病的风险。 过度饮酒者中的感染。滤泡辅助性T细胞(TFH)是一种CD4T细胞 在次级淋巴器官的生发中心反应中唯一发现。TFH的特殊功能 细胞是选择生发中心产生高亲和力抗体的B细胞。我们新奇的初步数据 首次展示了过量饮酒和酒精性肝病对循环TFH(CTFH)细胞的影响。在这 目的：我们假设过量饮酒会导致cTFH细胞分化改变，并且 这些对cTFH细胞的影响是增强的，并影响了AH患者的生存结果。我们将测试 (1)AH患者cTFH细胞功能紊乱；(2)AH患者存在T细胞内源性或T细胞外源性 改变cTFH细胞分化的缺陷，以及(Iii)AH患者继发性B细胞反应异常 与cTFH细胞的调节失调有关。我们的研究结果可能为通过靶向治疗急性肝炎提供参考。 免疫学途径与急性肝炎的发病机制有关。