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。鄙视它复杂的 发病机理，疾病过程中的关键驱动因素之一是先天和适应性免疫的改变 饮酒过量的回应。此申请是回应资金机会的 “酒精性肝炎临床和翻译网络 - 翻译研究（RFA-AA-18-003）”。目标 我们的应用是更好地了解先天和适应性免疫的作用和机制 酒精性肝炎的发病机理，因为这可能有助于我们确定新的治疗靶标，以治疗这种严重的治疗 Ald的形式。提出了两个具体目标：目标＃1：确定的影响和预后意义 AH患者的微生物易位，免疫失调和疾病严重程度的结果和结果。在 这个目的，我们假设（i）免疫失调的状态对基线疾病有影响 AH和（ii）随后的AH和（ii）持续免疫激活的患者的严重程度和长期结局 欲望的禁欲是AH患者的不利影响。我们发现乙醇素数 外周血单核细胞用于LPS诱导的炎症反应。在Sub-aim＃1.1中，我们将执行 基线肠道通透性，微生物易位，免疫细胞的细节横截面/纵向分析 健康对照中的激活/炎症，无肝病的ED和患有AH的炎症。我们还发现 AH患者的血浆IL-8是中性粒细胞的潜在趋化因子，显着升高。诱导 嗜中性粒细胞的肝脏炎症/损伤，含有线骨 - 含有线粒体-DNA 来自肝细胞的微粒（MPS）；永久性嗜中性粒细胞和肝损伤。在Sub-aim＃1.2中，我们将 确定IL-8和线粒体-DNA（MT-DNA）在AH患者中的作用和临床意义。 目标＃2：确定卵泡辅助T细胞改变的机制和意义 啊。关于酒精如何影响自适应免疫系统，不知道增加风险 过量饮酒的人的感染。卵泡T辅助器（TFH）细胞是CD4 T细胞谱系 在继发性淋巴器官的生发中心反应中独特发现。 TFH的特定功能 细胞是在生成高亲和力ABS的生发中心中选择B细胞。我们的新型初步数据 首次表明饮酒和ALD对循环TFH（CTFH）细胞的影响。在这个 目的，我们假设超级饮酒会导致CTFH细胞分化的改变，并且 这些对CTFH细胞的影响增加并影响AH患者的生存结果。我们将测试 （i）AH患者患有CTFH细胞失调，（ii）AH患者具有T细胞中的或T细胞 - 肢体的T细胞。 改变CTFH细胞分化的缺陷，以及（iii）AH患者的B细胞反应异常 在CTFH细胞中调节失调。我们的结果可能通过靶向特定来阐明AH的治疗 与AH的发病机理相关的免疫途径。