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

• 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
• 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

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、自身炎症性肝脏疾病， 免疫抑制剂是AIH患者唯一的治疗选择。肝脏炎症， 显性AIH阶段被认为是肝组织损伤和纤维化的主要驱动因素。虽然可逆， 如果不进行治疗，AIH会发展为肝硬化和终末期肝病，需要进行肝移植 在大约10%的情况下。其确切的触发因素和AIH发展的潜在机制很差 尽管遗传和环境因素起着重要作用，但我们对此并不了解。当地的肝脏微生物组 已被确定为调节肝脏病理的一个关键环境因素。扩大 微生物如乳酸杆菌属（Lactobacilli spp.）肝内的炎症与 实验肝脏病理学和乳酸杆菌属（Lactobacilli spp.）在AIH患者的肝脏中富集。我们的实验室最近 发表了罗伊氏乳杆菌（Lactobacillus reuteri（L. reuteri）易位到内部组织，从而驱动全身性 在造血细胞中缺乏表观遗传调节因子泰特甲基胞嘧啶双加氧酶2（Tet2）的小鼠中的炎症 细胞（Tet2VAV小鼠）。我们最近发现这种小鼠患有AIH，并且是研究这种疾病的模型系统， 流行病学证据支持TET2缺乏个体显示肝病的主要特征。 AIH的发病机制，特别是肝脏微生物组如何驱动它， 不清楚产生干扰素-γ（IFN-γ）的TCR γ CD8 T细胞（Tc1细胞）已被鉴定为在免疫调节中发挥重要作用。 在AIH中的作用缺少的是对来自肝脏微生物群的关键信号的理解，以及它们如何与 这种致病细胞的诱导。有趣的是，L。罗伊氏菌有效地分解代谢膳食色氨酸（Trp）， 芳香烃受体（AhR）激动剂吲哚-3-甲醇（I3C）。在狼疮模型中，来自于 e.鸡胚免疫促进Th17驱动的自身免疫。在这里，根据我们的新数据和来自 文献，我们提出了一个模型和可检验的假设解释如何L。reuteri促进AIH。我们将测试 中心假设L. reuteri通过释放I3C和/或提供L.罗伊，罗伊 在两个独立的AIH模型（Tet2VAV小鼠和伴刀豆球蛋白A介导的肝炎）中特异性Tc1细胞。 此外，我们认为抑制AhR信号传导的治疗方法可以保护L。路透社触发的 Tc1细胞介导的AIH样病理。我们将在三个具体目标中研究这一假设。在目标1中， 确定L.罗伊氏衍生的I3C通过AhR直接作用于CD8 T细胞，其促进Tc1细胞效应子 驱动AIH样病理的功能。在目标2中，我们将定义是否L。路透社特异性CD8 T细胞驱动AIH- 就像疾病在目标3中，我们将定义靶向CD8 T细胞内AhR信号传导的治疗方法（饮食疗法）。 Trp、AhR阻断）在防止AIH样病理中的作用。这些目标将有助于更好地了解 AIH的病理生理学，并评估AIH患者的合理治疗干预措施。