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.

项目总结

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