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

基本信息

批准号：
9791142
负责人：
Suthat Liangpunsakul
金额：
$ 19.58万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/9791142
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 Immune Cell Activation Immunologic Memory Immunologics Impairment Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Intestinal permeability Lead Light Link Lipopolysaccharides Liver diseases Lymphoid Malignant Neoplasms Morbidity - disease rate Natural Immunity Neutrophilia Organ 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 survival outcome

项目摘要

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.

项目概要尽管有并发症，酒精性肝炎仍是美国发病和死亡的主要原因。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)”。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提出了两个具体目标：目标#1：确定 ALD 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。为了实现这一目标，我们发现 (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，但乙醇仍对 AH 患者的预后产生不利影响。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/纵向分析我们还发现，健康对照、无肝病的 ED 以及 AH 患者中存在激活/炎症。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。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）；使中性粒细胞增多和肝损伤持续存在。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，尽管酒精会增加风险，但人们对酒精如何影响适应性免疫系统知之甚少。酗酒者中的滤泡 T 辅助细胞 (TFH) 细胞属于 CD4 T 细胞谱系。特有的发现于次级淋巴器官生发中心反应的TFH的特殊功能。细胞的目的是选择生发中心产生高亲和力抗体的 B 细胞。首次研究了过量饮酒和 ALD 对循环 TFH (cTFH) 细胞的影响。我们的目标是，过度饮酒会导致 cTFH 细胞分化，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。 (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 细胞反应异常我们的结果可能有助于通过靶向特定的方法治疗 AH。与 AH 发病机制相关的免疫学途径。