Innate Immunity and Mouse Model of Kawasaki Disease

先天免疫与川崎病小鼠模型

• 批准号: 7806595
• 负责人: Danica Jenine Schulte
• 金额: $ 12.97万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806595
• 关键词: Acute; Affect; Aneurysm; Arteries; Arteritis; Atherosclerosis; Blood Vessels; Bone Marrow; CD8B1 gene; Cardiovascular Diseases; Cell Extracts; Cell Maturation; Cell Wall; Cessation of life; Child; Childhood; Clinical; Controlled Study; Coronary; Coronary artery; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Endothelial Cells; Etiology; Goals; Heart Diseases; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intraperitoneal Injections; Investigation; Lactobacillus; Lactobacillus casei; Lead; Lesion; Light; Link; Manuscripts; Mediating; Mediator of activation protein; Modeling; Molecular; Mucocutaneous Lymph Node Syndrome; Mus; NF-kappa B; Natural Immunity; Nature; Pathogenesis; Pathology; Patients; Peptidoglycan; Play; Preventive Intervention; Publishing; Receptor Signaling; Reporting; Research Personnel; Role; Signal Transduction; Site; Syndrome; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Time; Toll-like receptors; Transgenic Mice; United States; Vascular Diseases; Vasculitis; Wild Type Mouse; arterial lesion; base; clinically relevant; cytokine; improved; in vitro testing; in vivo; insight; lipoteichoic acid; macrophage; mimicry; mouse model; premature atherosclerosis; prevent; programs; response

DESCRIPTION (provided by applicant): Kawasaki disease (KD) is the most common form of acquired heart disease in children, both the etiology and molecular mechanisms leading to the associated coronary arteritis remain unknown. Injection of a cell wall extract derived from Lactobacillus casei; LCCWE, into mice causes coronary arteritis that is histopathologically similar to the arteritis seen in KD, yet injection of a cell wall extract from a closely related strain Lactobacillus paracasei; LpCCWE, does not. The overall goal of this project is to define the molecular mechanisms by which LCCWE causes coronary arteritis, and to explain why LpCCWE does not. Our published data indicate that LCCWE potently induces NF-kB via TLR2 and MyD88 but not TLR4 in vitro (in murine and human macrophages and ECs) and in vivo (TLR2-/- and MyD88-/- mice do not develop coronary lesions). Our recent studies in humans and mice show marked accumulation of mature dendritic cells (DCs) in clinical KD lesions and in mouse arterial lesions after inoculation with LCCWE, suggesting that DCs play an important mechanistic role in coronary arteritis in both clinical KD and in the mouse model of LCCWE-induced arteritis. The hypotheses:(1) lipoteichoic acids and/or peptidoglycans specific to L. casei but not L. paracasei produce coronary arteritis but extracts from L. paracasei do not;(2) DCs are activated by these molecular components, and orchestrate immune response leading to coronary arteritis, and that DCs are essential in triggering this response. Thus, DCs may also play a similarly important function in clinical KD and could respond to DC-targeted therapies. Specific Aims:(1) To define the bioactive component(s) of LCCWE that mediate inflammatory responses and coronary arteritis in this model, and to determine the molecular basis for the differences in response between L. casei and L. paracasei cell wall extracts;(2) To determine whether L. casei and/or L. paracasei cell wall extracts can induce DC activation in vitro using wild type, TLR2-/-, TLR4-/-, and MyD88-/- DCs and to explore the role of DCs in mediating coronary arteritis in vivo using a DC depletion mouse model. Significance: Improved understanding of the molecular mechanisms by which LCCWE leads to coronary arteritis and the role of the innate immune system and DCs in this mouse models may yield important insights into the pathogenesis of arterial inflammatory diseases, and suggest new targets for intervention and prevention of coronary artery pathology in KD.

描述（由申请人提供）：川崎病（KD）是儿童获得性心脏病中最常见的形式，导致相关冠状动脉炎的病因和分子机制尚不清楚。注射从干酪乳杆菌中提取的细胞壁提取物；LCCWE注入小鼠引起冠状动脉炎，其组织病理学上与KD中所见的动脉炎相似，但注射一种密切相关的副干酪乳杆菌细胞壁提取物；LpCCWE则不然。该项目的总体目标是确定LCCWE引起冠状动脉炎的分子机制，并解释LpCCWE不引起冠状动脉炎的原因。我们发表的数据表明，LCCWE在体外（小鼠和人巨噬细胞和内皮细胞）和体内（TLR2-/-和MyD88-/-小鼠不发生冠状动脉病变）中通过TLR2和MyD88-/-有效诱导NF-kB，而不是TLR4。我们最近对人类和小鼠的研究表明，接种LCCWE后，成熟树突状细胞（dc）在临床KD病变和小鼠动脉病变中显著积累，这表明dc在临床KD和LCCWE诱导的小鼠模型冠状动脉炎中都起着重要的机制作用。假设：(1)干酪乳杆菌特有的脂质胆酸和/或肽聚糖产生冠状动脉炎，而副干酪乳杆菌不产生；(2)树突状细胞被这些分子成分激活，并协调导致冠状动脉炎的免疫反应，并且树突状细胞在触发这种反应中是必不可少的。因此，dc也可能在临床KD中发挥类似的重要功能，并可能对dc靶向治疗有反应。具体目的：(1)明确在该模型中LCCWE介导炎症反应和冠状动脉炎的生物活性成分，并确定干酪乳杆菌和副干酪乳杆菌细胞壁提取物反应差异的分子基础；(2)利用野生型、TLR2-/-、TLR4-/-和MyD88-/- DC在体外诱导DC活化，并通过DC耗竭小鼠模型探讨DC在体内介导冠状动脉炎中的作用。意义：进一步了解LCCWE导致冠状动脉炎的分子机制以及先天免疫系统和dc在该小鼠模型中的作用，可能对动脉炎症性疾病的发病机制有重要的认识，并为KD的冠状动脉病理干预和预防提供新的靶点。