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

T 辅助 2 炎症

• 批准号: 8286913
• 负责人: Gabriele Grunig
• 金额: $ 39.6万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/8286913
• 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

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，常见于在肺动脉中度过部分生命周期的蠕虫寄生虫感染（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，作为治疗与自身免疫等引起的严重炎症性疾病相关的肺动脉高压的新靶标。