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：
10490451
负责人：
Marlies Meisel
金额：
$ 45.38万
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/10490451
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 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 end stage liver disease genetic signature human disease immunoregulation improved inhibitor liver inflammation 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，自身炎症性肝脏疾病，经常变成对免疫抑制剂的难治性 - AIH患者的唯一治疗选择。肝炎症公开AIH的阶段被认为是肝组织损伤和纤维化的主要驱动力。虽然可逆，in 缺乏治疗AIH发展为肝硬化和终阶段肝病，需要肝移植在大约10％的情况下。它的确切触发因素以及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，但可理解的齿。局部肝微生物组具有被确定为调节肝病病理的一个关键环境因素。扩展共生细菌，例如乳酸杆菌。肝内的严重程度增加实验性肝病学和乳杆菌属。富含AIH患者的生活。我们最近的实验室发表说，乳酸杆菌Reuteri（L. Reuteri）转移到内部组织，从而驱动系统性缺乏表观遗传调节剂TET甲基胞嘧啶二加氧酶2（TET2）的小鼠的炎症细胞（TET2VAV小鼠）。我们最近发现，此类小鼠具有AIH，并且是研究这种疾病的模型系统，在流行病学证据的支持下，TET2特定个体表现出肝病的基本特征。 AIH背后的致病机制，尤其是肝微生物组如何驱动它，是不清楚。已经确定了产生TCRCD8T细胞（TC1细胞）的干扰素-γ（IFN-γ）以发挥必不可少的在AIH中的角色。缺少的是了解肝脏微生物群的主要信号及其如何链接到的关键信号这种病原细胞的诱导。有趣的是，L. Reuteri有效地分解了饮食色氨酸（TRP）芳基烃受体（AHR）激动剂吲哚-3-甲醇（I3C）。在狼疮模型中，AHR配体从 E. gallinarum促进了Th17驱动的自身免疫性。在这里，根据我们的新数据和此上下文文献，我们提出了一个模型和可检验的假设，解释了L. Reuteri如何促进AIH。我们将测试我们的中心假设是，L. Reuteri通过释放I3C和/或加油l。reuteri-来促进Hepatitic TC1细胞免疫力 AIH的两个独立模型（TET2VAV小鼠和canvalin a介导的肝炎）中的特定TC1细胞。此外，我们肯定地认为，抑制AHR信号的治疗方法可保护REUTERI-LI。 TC1细胞介导的AIH样病理。我们将以三个具体目标研究这一假设。在目标1中，我们将确定R. Reuteri衍生的I3C是否通过AHR直接在CD8 T细胞上作用，该细胞促进TC1细胞效应子驱动AIH样病理学的功能。在AIM 2中，我们将定义Reuteri特异性CD8 T细胞是否驱动AIH- 喜欢疾病。在AIM 3中，我们将定义针对CD8 T细胞内AHR信号传导的理论方法（饮食 TRP，AHR封锁）保护免受AIH样病理的影响。这些目标将使人们更好地理解 AIH的病理生理学和评估AIH患者的理由治疗干预措施。