T helper 2 Inflammation & Severe Muscularization of Arteries in the Lungs.

T 辅助 2 炎症

基本信息

批准号：
7985996
负责人：
Gabriele Grunig
金额：
$ 40万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7985996
关键词：
Ablation Acute Address Adoptive Transfer Affect Antibodies Antigens Arterial Injury Arteries Asthma Autoimmune Diseases Biological Response Modifiers C57BL/6 Mouse CD4 Positive T Lymphocytes Cells Childhood Chimeric Proteins Cigarette Smoker Clinical Data Companions Complement Complex Data Dendritic Cells Development Diagnosis Diphtheria Toxin Dirofilaria immitis Disease Evolution Goals Heart Helminths Human Hypertrophy Hypoxia ITGAX gene Immune Immune System Diseases Immune response Immunity Impairment Incidence Individual Infection Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Interleukin-1 Interleukin-13 Interleukin-17 Interleukin-4 Interleukins Laboratories Lesion Life Cycle Stages Lung Lung Inflammation Measurement Mediating Mediator of activation protein Mus Parasites Parasitic Diseases Parasitic infection Pathology Patients Phase Process Production Pulmonary Hypertension Pulmonary artery structure Recombinant Interleukin-13 Right Ventricular Function Role Scleroderma Severities Smooth Muscle Myocytes Systemic Scleroderma Systolic Pressure T cell response T-Lymphocyte Techniques Testing Time Transgenic Mice Ventricular Viral Wild Type Mouse Work abstracting arterial remodeling bronchial artery cytokine diphtheria toxin receptor hemodynamics member mortality mouse model outcome forecast promoter public health relevance pulmonary arterial hypertension receptor research study response time interval

项目摘要

DESCRIPTION (provided by applicant): T helper 2 Inflammation & Severe Muscularization of Arteries in the Lungs Project Summary / Abstract Pulmonary arterial remodeling, characterized by severe muscularization, is commonly seen in infections with helminth parasites that spend part of their life cycle in the pulmonary artery (e.g. Dirofilaria immitis). These parasites induce a T helper 2 (Th2) response. This same type of lesion is also seen in the bronchial artery in asthma, another Th2-response associated disease, particularly in individuals with asthma of long duration, or in asthmatic cigarette smokers. These associations indicate that severe muscularization of the pulmonary or bronchial arteries might be a consequence of a Th2 driven inflammation. Classically, severe pulmonary arterial muscularization has been described in pulmonary arterial hypertension (PAH). An immune-pathology has been suspected in PAH associated with autoimmune diseases such as systemic scleroderma, viral, or parasitic diseases. In preliminary experiments, we have shown that the Th2 response to soluble antigen alone is sufficient to induce severe pulmonary arterial muscularization and increased right ventricular systolic pressures following acute hypoxia. This was induced in immunized C57BL/6 mice that were given intermittent airway challenges over a prolonged period of time with either of two different antigens. CD4+ T cells and Interleukin (IL)-4 were necessary for the development of pulmonary arterial muscularization and transient depletion of an important Th2 cytokine, IL-13, decreased the severity of the lesion. IL-13 alone was not sufficient indicating that a complex Th2 - initiated process induced severe arterial muscularization. Which components of the Th2 response directly cause the arterial muscularization and how the Th2 response components interact are important questions yet to be answered. To address these questions, three specific aims are proposed to identify the roles of T cells and dendritic cells (DCs) and soluble immune mediators (IL-17, IL-33) for the effector phase during which arterial muscularization occurs. Experiments are proposed to deplete or to adoptively transfer T cells, dendritic cells, and soluble immune mediators during the time periods that arterial injury and remodeling occur in the lungs. Using techniques that are securely established in my laboratory, the hypothesis to be tested is that T cells and DCs control the production of IL-17 and IL-33 thereby directly determining the degree of pulmonary arterial muscularization and right ventricular function. The long range goal of this work takes advantage of the mouse model developed in my laboratory to identify targets for the diagnosis, prognosis and management for inflammation associated PAH, such as PAH seen in scleroderma patients. This is unique and significant because a large body of clinical data has suspected the involvement of the immune response, but has not yet dissected the causal relationship between the immune response and severe muscularization of arteries in the lungs. PUBLIC HEALTH RELEVANCE: T helper 2 inflammation & severe muscularization of arteries in the lungs Project Narrative Pulmonary arterial muscularization is a frequent histological lesion seen in pulmonary arterial hypertension (PAH). Severe arterial muscularization is also typical for diseases associated with T helper 2 (Th2) immune responses: helminth parasite infections, auto-immune diseases affecting pulmonary arteries and asthma affecting bronchial arteries. Building on our previous work developing Th2-immune-response induced mouse models of severe pulmonary arterial muscularization, this proposal seeks to identify T cell response controlled cells and mediators that are new targets for the management of pulmonary hypertension associated with severe inflammatory diseases caused for example by auto-immunity.

描述（由申请人提供）：T helper 2 肺部动脉炎症和严重肌化项目摘要/摘要肺动脉重塑，以严重肌化为特征，常见于在肺部度过部分生命周期的蠕虫寄生虫感染。动脉（例如恶丝虫）。这些寄生虫会诱导 T 辅助细胞 2 (Th2) 反应。这种相同类型的病变也见于哮喘（另一种 Th2 反应相关疾病）的支气管动脉中，特别是在患有长期哮喘的个体或患有哮喘的吸烟者中。这些关联表明，肺动脉或支气管动脉的严重肌化可能是 Th2 驱动的炎症的结果。传统上，严重的肺动脉肌化被描述为肺动脉高压（PAH）。人们怀疑 PAH 存在与自身免疫性疾病（如系统性硬皮病、病毒或寄生虫病）相关的免疫病理学。在初步实验中，我们已经表明，Th2 对可溶性抗原的单独反应足以诱导严重的肺动脉肌化和急性缺氧后右心室收缩压的增加。这是在免疫的 C57BL/6 小鼠中诱导的，这些小鼠在很长一段时间内用两种不同抗原之一进行间歇性气道挑战。 CD4+ T 细胞和白细胞介素 (IL)-4 对于肺动脉肌化的发展是必需的，而重要的 Th2 细胞因子 IL-13 的短暂消耗可降低病变的严重程度。单独的 IL-13 不足以表明复杂的 Th2 启动过程诱导了严重的动脉肌化。 Th2 反应的哪些成分直接导致动脉肌化以及 Th2 反应成分如何相互作用是有待回答的重要问题。为了解决这些问题，提出了三个具体目标，以确定 T 细胞和树突状细胞 (DC) 以及可溶性免疫介质（IL-17、IL-33）在动脉肌化发生的效应阶段的作用。建议在肺部发生动脉损伤和重塑期间进行实验，以消耗或过继转移 T 细胞、树突状细胞和可溶性免疫介质。使用我实验室已可靠建立的技术，要测试的假设是 T 细胞和 DC 控制 IL-17 和 IL-33 的产生，从而直接确定肺动脉肌化程度和右心室功能。这项工作的长期目标是利用我实验室开发的小鼠模型来确定与炎症相关的 PAH（例如硬皮病患者中出现的 PAH）的诊断、预后和治疗的目标。这是独特且重要的，因为大量临床数据怀疑免疫反应的参与，但尚未剖析免疫反应与肺部动脉严重肌化之间的因果关系。公共卫生相关性：T 辅助细胞 2 炎症和肺动脉严重肌化项目叙述肺动脉肌化是肺动脉高压 (PAH) 中常见的组织学病变。严重的动脉肌化也是与辅助 T 2 (Th2) 免疫反应相关的疾病的典型特征：蠕虫寄生虫感染、影响肺动脉的自身免疫性疾病和影响支气管动脉的哮喘。在我们之前开发 Th2 免疫反应诱导的严重肺动脉肌化小鼠模型的基础上，本提案旨在鉴定 T 细胞反应控制的细胞和介质，它们是治疗与严重炎症性疾病相关的肺动脉高压的新目标，例如通过自身免疫。