Role of Mucosal DC Subsets in the Control of Influenza A Virus Immunity

粘膜 DC 亚群在控制甲型流感病毒免疫中的作用

• 批准号: 8294597
• 负责人: MIRIAM MERAD
• 金额: $ 35.02万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294597
• 关键词: Address; Adult; Antigen-Presenting Cells; Antigens; Antiviral Agents; Asthma; Autoantigens; Biology; Bone Marrow; CD8B1 gene; Cell surface; Cellular Immunity; Cellular biology; Childhood; Chimera organism; Cytotoxic T-Lymphocytes; Data; Defense Mechanisms; Dendritic Cells; Development; Elements; Environment; Epithelial Cells; Generations; Guanine Nucleotide Dissociation Inhibitors; Homeostasis; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunologic Surveillance; Immunology; Influenza A virus; Institutes; Joints; Knock-out; Knockout Mice; Laboratories; Lead; Life; Link; Lung; Maintenance; Microbe; Modeling; Mus; Play; Population; Predisposition; Research; Research Personnel; Respiratory Syncytial Virus Infections; Role; Sampling; Structure of parenchyma of lung; System; Systems Biology; T-Lymphocyte; Tissues; Viral Antigens; Virus; Virus Diseases; Work; in vivo; influenzavirus; medical schools; member; mouse model; programs; respiratory; respiratory virus

DESCRIPTION (provided by applicant): Respiratory epithelial-cell surfaces present a large interface with the external environment and provide the first line of defense against a broad array of microbes. Initially perceived as a passive barrier between the host and the environment, the lung is now known to constitute a robust system of immune surveillance that include epithelial cells as well as highly specialized professional antigen presenting cells (APC) distributed throughout the conducting airways and the lung parenchyma. However, the critical elements required for development of protective immunity and the maintenance of immune homeostasis in the lung are largely unknown, particularly in the steady state in the human. This is important because uncontrolled or skewed immunity in the lung might lead to illness as for example might be the case in the link between RSV infection in childhood and increased susceptibility to asthma in adult life. Dendritic cells (DC) play a pivotal role in initiating the immune response to foreign antigens and in the maintenance of tolerance to self antigens. Drs Merad and Palucka laboratories have been working on the mechanisms that control the development and function of DC for more than ten years. Recent data from our groups revealed that the DC networks in nonlymphoid tissues consist of developmentally distinct and functionally specialized DC subsets in mice and humans. In this application, we propose to establish the functional specialization of the DC network in the lung and identify the mechanisms that control DC functional specialization in the induction of mucosal antiviral immunity. We will do so by studying mouse DC in vivo, human DC in humanized mice models as well as human lung. In our preliminary studies we have used influenza virus to probe the function of DC subsets in the lung. GFP-expressing virus differently interacts with distinct DC subsets. We show that distinct DC subsets preferentially interact with CD4+ or CD8+ T cells. These results support our hypothesis that the lung DC network consists of different subsets that differently control the induction of cellular and humoral immunity to respiratory viruses. Research proposed will be carried out through a collaborative effort between three established investigators with distinct and complementary expertise uniquely suited to address the central hypothesis of this application. The PI of this application, Dr. Miriam Merad (Mount Sinai School of Medicine (MSSM)) is an expert in mouse DC biology and has made several key contributions to our understanding of mucosal DC development and function in mice. Dr. Karolina Palucka (Joint investigator at Baylor Institute for Immunology Research (BUR) and MSSM) is a world expert in human DC biology and in humanized mouse models. Dr. Adolfo Garcia Sastre (MSSM) is a virologist and a world expert in influenza virus. In addition, Dr. Christian Becker (a pulmonologist at MSSM and a member of Merad's laboratory) has developed a strong human lung explants program with access to more than 100 fresh human lung samples per year.

描述（由申请人提供）：呼吸道上皮细胞表面与外部环境存在较大的界面，并提供针对多种微生物的第一道防线。最初被认为是宿主与环境之间的被动屏障，现在已知肺构成了强大的免疫监视系统，其中包括分布在整个传导气道和肺中的上皮细胞以及高度专业化的专业抗原呈递细胞（APC）薄壁组织。然而，肺部保护性免疫的发展和维持免疫稳态所需的关键要素在很大程度上尚不清楚，特别是在人体的稳定状态下。这一点很重要，因为肺部免疫力不受控制或倾斜可能会导致疾病，例如儿童时期 RSV 感染与成年后哮喘易感性增加之间的联系。树突状细胞（DC）在启动对外来抗原的免疫反应和维持对自身抗原的耐受性方面发挥着关键作用。 Merad 和 Palucka 博士的实验室十多年来一直致力于研究控制 DC 发育和功能的机制。我们小组的最新数据显示，非淋巴组织中的 DC 网络由小鼠和人类中发育独特且功能专门化的 DC 子集组成。在此应用中，我们建议建立肺中 DC 网络的功能特化，并确定在诱导粘膜抗病毒免疫过程中控制 DC 功能特化的机制。我们将通过研究小鼠 DC 体内、人源化小鼠模型中的人类 DC 以及人类肺部来实现这一目标。在我们的初步研究中，我们使用流感病毒来探测肺部 DC 亚群的功能。表达 GFP 的病毒与不同的 DC 亚群有不同的相互作用。我们发现不同的 DC 亚群优先与 CD4+ 或 CD8+ T 细胞相互作用。这些结果支持我们的假设，即肺 DC 网络由不同的子集组成，这些子集以不同的方式控制对呼吸道病毒的细胞和体液免疫的诱导。拟议的研究将通过三名既定的研究人员之间的合作来进行，这些研究人员具有独特且互补的专业知识，特别适合解决该应用的中心假设。该应用程序的 PI Miriam Merad 博士（西奈山医学院 (MSSM)）是小鼠 DC 生物学方面的专家，为我们了解小鼠粘膜 DC 的发育和功能做出了多项关键贡献。 Karolina Palucka 博士（贝勒免疫学研究所 (BUR) 和 MSSM 联合研究员）是人类 DC 生物学和人源化小鼠模型领域的世界专家。阿道夫·加西亚·萨斯特雷 (Adolfo Garcia Sastre) 博士 (MSSM) 是一位病毒学家，也是流感病毒领域的世界专家。此外，Christian Becker 博士（MSSM 的肺科医生，Merad 实验室的成员）开发了强大的人肺外植体计划，每年可以获得 100 多个新鲜人肺样本。