Innate immune regulation of inflammation and adaptive immunity

炎症的先天免疫调节和适应性免疫

• 批准号: 7651357
• 负责人: Anthony L Defranco
• 金额: $ 181.77万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651357
• 关键词: Innate; immune; regulation; inflammation; adaptive

DESCRIPTION (provided by applicant): In recent years, Innate Immunity has gone from being the "immunologists' dirty little secret" to being among the most active and exciting areas of immunology. Many recognition molecules of vertebrate innate immune cells have been defined and much is now known about their mechanisms of action. Nonetheless, much remains to be learned before we truly understand how to harness these mechanisms for vaccination and cancer immunotherapy or how to block them to treat autoimmune and inflammatory disease. This proposed Program Project combines 4 investigators with established expertise in the area of innate immunity to pursue related studies developing out of their independent research efforts, but containing numerous connections and great potential for combined effort. In Project #1, Dr. DeFranco will utilize his newly created conditional allele of myd88 to dissect the cellular basis of Toll-like receptor signaling for systemic and mucosal immune responses, with emphasis on airways and fungal infections. In Project #2, Dr. Ma will analyze the role of the ubiquitin-modifying regulator A20 in dendritic cells for restraining TLR responses and preventing inflammatory disease. In Project #3, Dr. Lowell will determine the mechanism by which myeloid cells contribute to lupus-like autoimmunity in the Lyn-deficient mouse model. Finally, in Project #4, Dr. Locksley will determine how chitin, a polysaccharide found in fungi and invertebrates, promotes type 2 immunity and how it interacts with TLR signaling pathways to regulate the type of immune response. Lay Language: The immune system recognizes conserved elements of viruses, bacteria, fungi and multicellular invertebrates to allow it to detect infections and fight them. Immunologists are defining a number of the molecular mechanisms by which this is done, but much remains to be learned, particularly to understand how these reactions are controlled to avoid excessive inflammation and tissue injury, while directing the immune system toward the type of immune response most beneficial for fighting the infectious agent that is present. Better understanding of these issues will lead to improved vaccination procedures and better ability to control excessive inflammatory conditions. PROJECT 1: Cellular Basis of TLR signaling for Mucosal Immune Responses (DeFranco, A.) DESCRIPTION (provided by applicant): In recent years, Toll-like receptors (TLRs) have emerged as critical recognition elements of innate immunity, both for induction of inflammation at the site of an infection and for induction of an adaptive immune response. These receptors are expressed on the three major types of immune cells in many tissues, immature dendritic cells, tissue macrophages, and mast cells, as well as on several other types of cells. In the proposed project, we shall define which type of cell is responsible for mediating several TLR-based immune responses, systemically and in the airways. In these studies, we shall take advantage of a conditional allele we have engineered into the mouse germ line for the key TLR signaling adaptor molecule MyD88. This allows us to delete the gene encoding MyD88 specifically in particular cell types including dendritic cells, macrophages and neutrophils, B cells, and T cells. In Aim 1, we shall determine the role of dendritic cells in a mouse model of allergic asthma in which antigen + TLR ligands are introduced via the airways. In Aim 2, we shall analyze the immune response of mice to systemic or airway exposure to zymosan, a yeast cell wall preparation that is composed of chitin, ligands for TLR2 and ligands for C-type lectin receptors (dectin-1, etc.). We shall dissect the roles that these different innate immune ligands play in directing the nature of the immune response between Th1, Th2 and Th17. The contributions of particular cell types will also be determined. Finally, in Aim 3, we'll determine the cell type-specific roles of MyD88 in host defense to systemic infection by the fungal pathogen, Candida albicans. Lay Language Summary: The proposed studies will determine which immune cells in tissues are responsible for initiating immune responses to inhaled antigens as a model of allergic asthma, to infections with yeasts and molds. This will be accomplished by the use of genetically modified mice, in which key immune cell types are unable to recognize the presence of fungal cell walls. These studies will be useful for improving vaccination strategies and for developing novel strategies to block inflammation for patients with inflammatory diseases.

描述（由申请人提供）：近年来，先天免疫从成为“免疫学家的肮脏小秘密”变成了最活跃和令人兴奋的免疫学领域。已经定义了脊椎动物先天免疫细胞的许多识别分子，现在已经了解了它们的作用机理。尽管如此，在我们真正了解如何利用这些机制进行疫苗接种和癌症免疫疗法或如何阻止它们以治疗自身免疫和炎症性疾病之前，还有很多待了解。该提议的计划项目将4位研究人员与先天免疫领域的既定专业知识相结合，以从其独立的研究工作中进行相关研究，但包含许多联系和巨大的努力潜力。在项目＃1中，DeFranco博士将利用其新创建的MyD88条件等位基因来剖析全身和粘膜免疫反应的Toll样受体信号传导的细胞基础，重点是气道和真菌感染。在项目＃2中，MA博士将分析泛素修改调节剂A20在树突状细胞中的作用，以限制TLR反应并预防炎症性疾病。在项目＃3中，Lowell博士将确定髓样细胞在Lyn缺陷小鼠模型中导致类似狼疮的自身免疫的机制。最后，在项目＃4中，Locksley博士将确定在真菌和无脊椎动物中发现多糖浆的几丁素如何促进2型免疫力及其与TLR信号通路的相互作用如何调节免疫反应的类型。外行语言：免疫系统识别病毒，细菌，真菌和多脊椎动物的保守元素，以使其能够检测感染并与之抗争。免疫学家正在定义这样做的许多分子机制，但仍有许多待了解，尤其是了解如何控制这些反应以避免过度的炎症和组织损伤，同时将免疫系统引导到免疫反应的类型最有益，最有益地对现有的感染剂作斗争。更好地了解这些问题将导致改善疫苗接种程序和更好地控制过度炎症状况的能力。 项目1：粘膜免疫反应的TLR信号传导的细胞基础（Defranco，A。） 描述（由申请人提供）：近年来，Toll样受体（TLR）已成为先天免疫的关键识别要素，既可以在感染部位诱导炎症，又是诱导适应性免疫反应。这些受体在许多组织，未成熟的树突状细胞，组织巨噬细胞和肥大细胞以及其他几种细胞的三种主要类型的免疫细胞上表达。在拟议的项目中，我们将定义哪种类型的细胞负责系统地和气道中介导几种基于TLR的免疫反应。在这些研究中，我们将利用有条件的等位基因，用于将键TLR信号适配器分子MyD88设计到小鼠生殖系中。这使我们能够在特定细胞类型中删除编码MYD88的基因，包括树突状细胞，巨噬细胞和中性粒细胞，B细胞和T细胞。在AIM 1中，我们将确定树突状细胞在通过气道引入抗原 + TLR配体的过敏性哮喘模型中的作用。在AIM 2中，我们将分析小鼠对全身或气道暴露于Zymosan的免疫反应，Zymosan是酵母细胞壁制剂，该酵母细胞壁制剂由几架，TLR2的配体和C型凝集素受体（Dectin-1等）组成。我们将剖析这些不同的先天免疫配体在指导Th1，Th2和Th17之间的免疫反应性质中发挥的作用。还将确定特定细胞类型的贡献。最后，在AIM 3中，我们将确定MyD88在宿主防御中的细胞类型特异性作用。外行语言摘要：拟议的研究将确定组织中哪些免疫细胞负责引发对吸入抗原作为过敏性哮喘模型的免疫反应，以感染酵母和霉菌。这将通过使用转基因小鼠来实现，其中关键免疫细胞类型无法识别出真菌细胞壁的存在。这些研究将有助于改善疫苗接种策略和制定新的策略来阻止炎症性疾病患者的炎症。