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: 10440367
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440367
• 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; 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 inflammation; 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.

项目概要 酒精性肝炎是美国发病和死亡的主要原因。尽管其复杂 发病机制中，疾病过程的关键驱动因素之一是先天性和适应性免疫的改变 过度饮酒引起的继发反应。此申请是为了响应资助机会 “酒精性肝炎临床和转化网络 - 转化研究 (RFA-AA-18-003)”。目标 我们应用的目的是更好地了解先天性和适应性免疫在 酒精性肝炎的发病机制，因为这可能有助于我们确定治疗这种严重疾病的新治疗靶点 ALD 的形式。提出了两个具体目标： 目标#1：确定以下因素的影响和预后意义： 微生物易位、免疫失调对 AH 患者疾病严重程度和结果的影响。在 为了实现这一目标，我们假设 (i) 免疫失调状态对基线疾病有影响 AH 患者的严重程度和长期结果以及（ii）后续期间持续的免疫激活 尽管禁欲，AH 患者的预后仍会受到不利影响。我们发现乙醇引发 外周血单核细胞对 LPS 诱导的炎症反应的影响。在子目标#1.1中，我们将执行 关于基线肠道通透性、微生物易位、免疫细胞的详细横断面/纵向分析 健康对照、无肝病的 ED 以及患有 AH 的患者中存在激活/炎症。我们还发现 血浆 IL-8（中性粒细胞的一种有效趋化因子）在 AH 患者中显着升高。感应 中性粒细胞的释放导致肝脏炎症/损伤，其中含有线粒体 DNA 来自肝细胞的微粒（MP）；持续中性粒细胞增多和肝损伤。在子目标#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：确定患有以下疾病的患者滤泡辅助 T 细胞改变的机制和意义 啊。尽管酒精会增加患病风险，但人们对酒精如何影响适应性免疫系统知之甚少。 过度饮酒者中的感染。滤泡辅助 T (TFH) 细胞是 CD4 T 细胞谱系 独特地发现于次级淋巴器官的生发中心反应。 TFH的具体功能 cells的作用是选择生发中心产生高亲和力抗体的B细胞。我们新颖的初步数据 首次显示过量饮酒和 ALD 对循环 TFH (cTFH) 细胞的影响。在这个 为此，我们假设过量饮酒会导致 cTFH 细胞分化发生改变，并且 这些对 cTFH 细胞的影响会增强并影响 AH 患者的生存结果。我们将测试 (i) AH 患者存在 cTFH 细胞失调，(ii) AH 患者存在 T 细胞内在或 T 细胞外在 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 cTFH 细胞失调。我们的结果可能会通过针对特定的靶标来治疗 AH 与 AH 发病机制相关的免疫学途径。

项目成果

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

• DOI: 10.1016/j.jhep.2021.10.005
• 发表时间: 2022-03
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Whitfield JB;Schwantes-An TH;Darlay R;Aithal GP;Atkinson SR;Bataller R;Botwin G;Chalasani NP;Cordell HJ;Daly AK;Day CP;Eyer F;Foroud T;Gleeson D;Goldman D;Haber PS;Jacquet JM;Liang T;Liangpunsakul S;Masson S;Mathurin P;Moirand R;McQuillin A;Moreno C;Morgan MY;Mueller S;Müllhaupt B;Nagy LE;Nahon P;Nalpas B;Naveau S;Perney P;Pirmohamed M;Seitz HK;Soyka M;Stickel F;Thompson A;Thursz MR;Trépo E;Morgan TR;Seth D;GenomALC Consortium
• 通讯作者: GenomALC Consortium

Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol-Associated Hepatitis.

• DOI: 10.1002/hep.31994
• 发表时间: 2021-11
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Yang Z;Zhang T;Kusumanchi P;Tang Q;Sun Z;Radaeva S;Peiffer B;Shah VH;Kamath P;Gores GJ;Sanyal A;Chalasani N;Jiang Y;Huda N;Ma J;Liangpunsakul S
• 通讯作者: Liangpunsakul S

Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes.

• DOI: 10.1016/j.jhep.2021.02.004
• 发表时间: 2021-07
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: He Y;Feng D;Hwang S;Mackowiak B;Wang X;Xiang X;Rodrigues RM;Fu Y;Ma J;Ren T;Ait-Ahmed Y;Xu M;Liangpunsakul S;Gao B
• 通讯作者: Gao B

Intestinal dendritic cells, gatekeepers preventing ethanol-induced liver disease.

肠道树突状细胞，预防乙醇引起的肝病的看门人。

• DOI: 10.1097/hep.0000000000000236
• 发表时间: 2023
• 期刊: Hepatology (Baltimore, Md.)
• 作者: Llorente,Cristina;Rungratanawanich,Wiramon;Liangpunsakul,Suthat
• 通讯作者: Liangpunsakul,Suthat

Role of endotoxemia in causing renal dysfunction in cirrhosis.

• DOI: 10.1136/jim-2019-001056
• 发表时间: 2020-01
• 期刊: Journal of investigative medicine : the official publication of the American Federation for Clinical Research
• 作者: Peng JL;Techasatian W;Hato T;Liangpunsakul S
• 通讯作者: Liangpunsakul S