Systemic immunoregulatory consequences of bacterial translocation during health and disease

健康和疾病期间细菌易位的全身免疫调节后果

基本信息

批准号：
10339088
负责人：
Marlies Meisel
金额：
$ 45.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10339088
关键词：
Affect Agonist Antibiotic Therapy Antigens Aryl Hydrocarbon Receptor Autoimmune Hepatitis Autoimmunity Automobile Driving Bacterial Translocation Biological Models CD8-Positive T-Lymphocytes Cell Differentiation process Cells Chronic Cirrhosis Clonal Expansion Clone Cells Concanavalin A Data Dependence Diet Dioxygenases Disease Effector Cell Environmental Risk Factor Epidemiology Epigenetic Process Fibrosis Functional disorder Genetic Genetic Predisposition to Disease Genetic Transcription Germ-Free Health Hematopoietic Hepatic Hepatic Tissue Hepatitis Hepatocyte Human Immune Immunity Immunosuppressive Agents Individual Indole-3-Carbinol Inflammation Interferon Type II Interferons Knowledge Lactobacillus Lactobacillus reuteri Link Literature Liver Liver Fibrosis Liver diseases Lupus Mediating Mission Modeling Mus National Institute of Diabetes and Digestive and Kidney Diseases Pathogenicity Pathology Patients Play Production Publishing Receptor Inhibition Receptor Signaling Refractory Role Severities Signal Transduction TC1 Cell Testing Tetanus Helper Peptide Therapeutic Therapeutic Intervention Tissues Treatment Efficacy Tryptophan Wild Type Mouse Work aryl hydrocarbon receptor ligand autoinflammatory base commensal bacteria dietary genetic signature human disease immunoregulation improved inhibitor/antagonist liver injury liver transplantation microbiome microbiota pre-clinical programs public health relevance systemic inflammatory response

项目摘要

Autoimmune hepatitis (AIH) is a chronic, progressive, auto-inflammatory liver disorder that often becomes refractory to immunosuppressants-the sole therapeutic option for AIH patients. Hepatic inflammation, which sets the stage for overt AIH, is considered the main driver of hepatic tissue damage and fibrosis. While reversible, in the absence of treatment AIH progresses to cirrhosis and end stage liver disease, requiring liver transplantation in around 10% of cases. Its exact trigger and the underlying mechanisms by which AIH develops are poorly understood, although genetic and environmental factors play an important role. The local liver microbiome has been identified as one critical environmental factor that modulates hepatic pathology. The expansion of commensal bacteria such as Lactobacilli spp. within the liver is associated with an increased severity of experimental liver pathology, and Lactobacilli spp. are enriched in livers of AIH patients. Our lab recently published that Lactobacillus reuteri (L. reuteri) translocates to internal tissues and thereby drives systemic inflammation in mice that lack the epigenetic regulator Tet methylcytosine dioxygenase 2 (Tet2) in hematopoietic cells (Tet2VAV mice). We recently found that such mice have AIH and are a model system to study this disease, supported by epidemiological evidence that TET2 deficient individuals display cardinal features of liver disease. The pathogenetic mechanisms underlying AIH, and in particular how the liver microbiome may drive it, are unclear. Interferon- γ (IFN-γ) producing TCR CD8 T cells (Tc1 cells) have been identified to play an essential role in AIH. Missing is an understanding of the key signals from the liver microbiota and how they are linked to the induction of such pathogenic cells. Intriguingly, L. reuteri efficiently catabolizes dietary tryptophan (Trp) to the aryl hydrocarbon receptor (AhR) agonist indole-3-carbinol (I3C). In a lupus model, AhR ligands derived from E. gallinarum promoted Th17-driven autoimmunity. Here, based on our new data and this context from the literature, we propose a model and testable hypothesis explaining how L. reuteri promotes AIH. We will test our central hypothesis that L. reuteri promotes hepatic Tc1 cell immunity by releasing I3C and/or by fueling L. reuteri- specific Tc1 cells in two independent models of AIH (Tet2VAV mice and Concanavalin A-mediated hepatitis). Furthermore, we posit that therapeutic approaches that suppress AhR signaling protect from L. reuteri-triggered Tc1 cell mediated AIH-like pathology. We will investigate this hypothesis in three specific aims. In Aim 1 we will determine whether L. reuteri derived I3C acts directly on CD8 T cells via AhR, which promotes Tc1 cell effector function that drives AIH-like pathology. In Aim 2 we will define whether L. reuteri-specific CD8 T cells drive AIH- like disease. In Aim 3 we will define therapeutic approaches targeting AhR signaling within CD8 T cells (dietary Trp, AhR blockade) in protecting from AIH-like pathology. These aims will lead to a better understanding of the pathophysiology of AIH and assess rationale therapeutic interventions for patients with AIH.

自身免疫性肝炎 (AIH) 是一种慢性、进行性、自身炎症性肝病，通常会发展为免疫抑制剂难以治疗——AIH 患者的唯一治疗选择，从而引发了肝脏炎症。明显的 AIH 阶段被认为是肝组织损伤和纤维化的主要驱动因素，虽然是可逆的。缺乏治疗 AIH 会进展为肝硬化和终末期肝病，需要肝移植大约 10% 的病例中，AIH 的确切触发因素和潜在机制尚不明确。据了解，尽管遗传和环境因素发挥着重要作用，但局部肝脏微生物群却起着重要作用。已被确定为调节肝脏病理学扩展的一个关键环境因素。肝脏内的共生细菌（例如乳酸杆菌）与病情严重程度的增加有关。实验性肝脏病理学显示，我们的实验室最近在 AIH 患者的肝脏中富集了乳酸菌。发表了罗伊氏乳杆菌 (L. reuteri) 易位至内部组织并驱动全身造血系统中缺乏表观遗传调节剂 Tet 甲基胞嘧啶双加氧酶 2 (Tet2) 的小鼠的炎症我们最近发现此类小鼠患有 AIH，并且是研究这种疾病的模型系统，流行病学证据表明 TET2 缺陷个体表现出肝病的主要特征。 AIH 的致病机制，特别是肝脏微生物组如何驱动它，是目前尚不清楚，产生 TCR CD8 T 细胞（Tc1 细胞）的干扰素-γ (IFN-γ) 发挥着重要作用。缺乏对肝脏微生物群关键信号及其相互关系的了解。有趣的是，罗伊氏乳杆菌能有效地将饮食中的色氨酸 (Trp) 分解代谢为芳烃受体 (AhR) 激动剂吲哚-3-甲醇 (I3C) 在狼疮模型中，AhR 配体衍生自。在此，基于我们的新数据和来自 Th17 的背景，鸡肠杆菌促进了 Th17 驱动的自身免疫。文献中，我们提出了一个模型和可检验的假设来解释罗伊氏乳杆菌如何促进 AIH。我们将测试我们的结果。中心假设是罗伊氏乳杆菌通过释放 I3C 和/或通过为罗伊氏乳杆菌提供能量来促进肝 Tc1 细胞免疫两个独立的 AIH 模型（Tet2VAV 小鼠和刀豆球蛋白 A 介导的肝炎）中的特异性 Tc1 细胞。此外，我们假设抑制 AhR 信号传导的治疗方法可以防止罗伊氏乳杆菌触发 Tc1 细胞介导的 AIH 样病理学在目标 1 中我们将研究这一假设。确定罗伊氏乳杆菌衍生的 I3C 是否通过 AhR 直接作用于 CD8 T 细胞，从而促进 Tc1 细胞效应子在目标 2 中，我们将定义罗伊氏乳杆菌特异性 CD8 T 细胞是否驱动 AIH- 在目标 3 中，我们将定义针对 CD8 T 细胞（饮食）内的 AhR 信号传导的治疗方法。 Trp、AhR 阻断）在预防 AIH 样病理方面的作用将有助于更好地理解 AIH 样病理。 AIH 的病理生理学并评估 AIH 患者的基本治疗干预措施。