Targeting innate lymphoid cells during influenza virus-induced asthma

在流感病毒诱发的哮喘期间靶向先天淋巴细胞

• 批准号: 8566307
• 负责人: DALE T UMETSU
• 金额: $ 16.94万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566307
• 关键词: Acute; Address; Adrenal Cortex Hormones; Affect; Alveolar Macrophages; Asthma; Biology; Categories; Cells; Cessation of life; Child; Clinical; Complex; Data; Development; Dose; Elderly; Epithelial Cells; Experimental Models; General Population; Goals; Health; Helper-Inducer T-Lymphocyte; Hospitalization; Human; Imatinib; Immune; Immunobiology; Infection; Inflammation; Influenza; Interleukin-13; Intervention; Lead; Lung; Lung diseases; Lymphoid Cell; Mediating; Mucosal Immune Responses; Mus; National Institute of Allergy and Infectious Disease; New England; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Population; Pregnant Women; Production; Proto-Oncogene Protein c-kit; Public Health; Role; Stem Cell Factor; TSLP gene; Th2 Cells; Therapeutic; Vaccines; Viral; Virus; Virus Diseases; adaptive immunity; airway hyperresponsiveness; airway inflammation; base; biodefense; cell type; cost; cytokine; flu activity; high risk; improved; influenzavirus; inhibitor/antagonist; insight; kinase inhibitor; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; pandemic disease; pathogen; preclinical study; prevent; response; swine flu

The long-term goal of this project is to develop better therapies for acute influenza virus-induced respiratory disease and asthma. Influenza virus (an NIAID Category C pathogen) causes infection that is major public health problem, resulting in about 40,000 deaths and more than 200,000 hospitalizations annually in the US, with a total cost of over $10 billion/year. The 2009 swine flu pandemic demonstrated that patients with asthma are at particularly high risk for developing severe influenza infection, associated with hospitalization and death. As the numbers reflect, current therapies for acute influenza-induced respiratory disease are not fully effective, in part because the host-influenza interactions resulting in, and mechanisms by which influenza infection causes, acute respiratory disease and asthma are not fully understood. In Specific Aim 1 we will examine a specific intervention that targets a novel innate lymphoid cell type in the lungs, called natural helper cells or nuocytes. We recently showed that natural helper cells are specifically activated during influenza infection and are required for influenza-induced asthma in mice. We will use a unique experimental model of influenza-induced airway inflammation and airway hyperreactivity (AHR) (a cardinal feature of asthma) that develops independently of Th2 cells and adaptive immunity, and which may reflect human influenza-induced respiratory disease and asthma. The response is initiated when influenza infects alveolar macrophages, leading to pyroptosis and release of IL-33, which then activates natural helper cells to produce IL-13, which in turn mediates acute AHR. We will demonstrate that by targeting natural helper cells with c-Kit kinase inhibitors (imatinib or masitinib), influenza-induced airway pathology can be abolished. Such therapy may be much more effective than high dose corticosteroids, commonly used in patients with influenza-induced asthma. In Specific Aim 2 we will further refine the approach of targeting natural helper cells during influenza infection, and examine the interaction of influenza with host cells resulting in the production of IL-33, IL-25, and TSLP. All three of these cytokines potently activate natural helper cells, inducing them to produce IL-13. These studies will define host-influenza interactions and the biology of natural helper cells in this complex innate pathway, described only one year ago. Understanding the many components of this pathway is critical to provide key insights into how c-Kit kinase inhibitors fit into this pathway to reduce natural helper cell activity and influenza-induced asthma. These studies will focus on developing a novel therapeutic for acute, influenza-induced respiratory disease and asthma, which are serious, common clinical problems. The proposed therapeutic will target a host cell type activated by influenza and required for its pathogenesis. Moreover, study of this therapy will extend our fundamental understanding of mucosal immune responses.

该项目的长期目标是开发更好的治疗方法来治疗急性流感病毒引起的呼吸道疾病 疾病和哮喘。流感病毒（NIAID C 类病原体）引起主要公众感染 健康问题，每年导致美国约 40,000 人死亡和超过 200,000 人住院， 每年总成本超过100亿美元。 2009 年猪流感大流行表明，患有以下疾病的患者 哮喘患者发生严重流感感染的风险特别高，且与住院相关 和死亡。正如数字所反映的，目前针对急性流感引起的呼吸道疾病的治疗方法并不有效。 完全有效，部分原因是宿主与流感的相互作用以及其机制 流感、急性呼吸道疾病和哮喘感染的原因尚不完全清楚。 在具体目标 1 中，我们将研究针对一种新型先天淋巴细胞类型的具体干预措施。 肺部，称为自然辅助细胞或核细胞。我们最近证明自然辅助细胞 在流感感染期间特别激活，并且是流感诱发的小鼠哮喘所必需的。我们 将使用流感引起的气道炎症和气道高反应性的独特实验模型 (AHR)（哮喘的一个主要特征）独立于 Th2 细胞和适应性免疫而发展，以及 这可能反映了人类流感引起的呼吸道疾病和哮喘。当以下情况时启动响应： 流感病毒感染肺泡巨噬细胞，导致焦亡并释放 IL-33，然后激活 自然辅助细胞产生 IL-13，进而介导急性 AHR。我们将证明通过 使用 c-Kit 激酶抑制剂（伊马替尼或马赛替尼）靶向天然辅助细胞、流感诱导的气道 病理可以被废除。这种疗法可能比高剂量皮质类固醇更有效， 常用于流感引起的哮喘患者。 在具体目标 2 中，我们将进一步完善在流感期间靶向自然辅助细胞的方法 感染，并检查流感与宿主细胞的相互作用，导致产生 IL-33、IL-25、 和 TSLP。所有这三种细胞因子都能有效激活天然辅助细胞，诱导它们产生 IL-13。 这些研究将定义宿主与流感的相互作用以及该复合物中自然辅助细胞的生物学 先天途径，仅在一年前描述过。了解该途径的许多组成部分是 对于提供有关 c-Kit 激酶抑制剂如何融入该途径以减少自然辅助细胞的关键见解至关重要 活动和流感引起的哮喘。这些研究将重点开发一种新的治疗方法，用于治疗急性、 流感引起的呼吸道疾病和哮喘是严重的常见临床问题。这 拟议的治疗方法将针对由流感激活且其发病机制所需的宿主细胞类型。 此外，对该疗法的研究将扩展我们对粘膜免疫反应的基本理解。