Dendritic cell produced IL-33 in Th2 responses

树突状细胞在 Th2 反应中产生 IL-33

• 批准号: 8104938
• 负责人: Anne I. Sperling
• 金额: $ 22.86万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104938
• 关键词: Address; Affect; Agonist; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Asthma; Basic Science; Bone Marrow; Breathing; Cells; Child; Clinic; Clinical Medicine; Data; Dendritic Cells; Development; Disease; Enzyme-Linked Immunosorbent Assay; Extrinsic asthma; Fc Receptor; Gene Expression Regulation; Genes; Hypersensitivity; IgE; Immune; Immune response; Immunoglobulin G; In Vitro; Individual; Inflammation; Inflammatory Response; Laboratories; Lead; Mediating; Modeling; Mus; Pathogenesis; Phenotype; Physiologic pulse; Play; Population; Precipitating Factors; Production; Regulation; Resources; Role; Sampling; Serum; Signal Transduction; Stimulus; T cell differentiation; T-Lymphocyte; TLR4 gene; Testing; Th2 Cells; Therapeutic Intervention; Up-Regulation; airway inflammation; base; crosslink; cytokine; in vivo; innovation; insight; mouse model; novel; receptor; research study; respiratory; response; tool; uptake

DESCRIPTION (provided by applicant): Asthma and allergy affect an estimated 600 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Our current understanding of these diseases demonstrates that Th2 cells play a major role in the inflammatory responses. However, the factors that induce T cells to differentiate towards a Th2 phenotype remain one of the important unresolved problems in these diseases. There is an established role of IgE in the pathogenesis of asthma and allergic disorders, but antigen-specific IgG is also present in large quantities in the serum of these individuals. We have previously found a novel role for the IgG activating receptor, Fc?RIII, in the regulation of Th2-dependent inflammation in a mouse model. Our findings that previous sensitization, which leads to antigen-specific IgG, could change the response of antigen-presenting cells may provide a new paradigm for therapeutic interventions. Previously, it was believed that antigen-presenting cells in both primary and secondary responses responded similarly stimuli such as TLR agonist. However, our findings now demonstrate that when antigen uptake is mediated by immune complexes instead of simple soluble antigen uptake, the TLR stimulated-DCs produce a differential gene profile that includes the up-regulation of IL-33 cytokine production. Our overall hypothesis is that antigen-specific IgG crosslinking of Fc?R increases Th2-immune responses, in part, through the production of IL-33 by DC. We propose the following specific aims: Aim #1: Determine the role of IL-33 in the augmented Th2 responses produced by immune-complex signaled bone marrow derived DC in vitro and in vivo. In this Aim, we propose to investigate the hypothesis that IL-33 production by BMDCs, directly or indirectly, induces augmented Th2 responses. Aim #2: Determine whether IL-33 is produced by innate immune cells through Fc?R signaling in vivo. In this Aim, we propose to investigate the hypothesis that Fc?R signaling on endogenous TLR4 activated respiratory DCs induces IL-33 production, which in turn augments Th2-mediated inflammation. Our studies will have a significant impact on our understanding of IgG modulation of DC function and how it affects Th2-mediated diseases. Further, we will gain valuable insight into the mechanisms regulating DC-mediated T cell differentiation and have the potential to identify novel targets for therapy in the clinic. In our laboratory, we have the expertise to successfully analyze Th2- mediated airway inflammation in vivo, and all the necessary resources and tools to complete the aims of this proposal. Further, we have made an innovative discovery that DC activation and gene regulation in secondary responses may be influenced by the presence of antigen specific IgG. PUBLIC HEALTH RELEVANCE: Asthma and allergy affect an estimated 600 million people worldwide and represent an important challenge for basic science to benefit clinical medicine. Children are a major and growing population of asthma sufferers. Our studies investigate the mechanisms by which hyper-immune response lead to asthma and allergies.

描述（由申请人提供）：哮喘和过敏症影响着全球约 6 亿人，是基础科学造福于临床医学的一项重要挑战。我们目前对这些疾病的了解表明，Th2 细胞在炎症反应中发挥着重要作用。然而，诱导 T 细胞分化为 Th2 表型的因素仍然是这些疾病中尚未解决的重要问题之一。 IgE 在哮喘和过敏性疾病的发病机制中发挥着明确的作用，但抗原特异性 IgG 也大量存在于这些个体的血清中。我们之前在小鼠模型中发现了 IgG 激活受体 Fc?RIII 在调节 Th2 依赖性炎症中的新作用。我们的研究结果表明，先前的致敏作用会导致抗原特异性 IgG 的产生，从而改变抗原呈递细胞的反应，这可能为治疗干预提供新的范例。此前，人们认为初次和二次反应中的抗原呈递细胞对 TLR 激动剂等刺激物的反应相似。然而，我们现在的研究结果表明，当抗原摄取是由免疫复合物介导而不是简单的可溶性抗原摄取时，TLR刺激的DC产生差异基因谱，其中包括IL-33细胞因子产生的上调。我们的总体假设是，Fc?R 的抗原特异性 IgG 交联部分地通过 DC 产生 IL-33 来增加 Th2 免疫反应。我们提出以下具体目标： 目标#1：确定 IL-33 在体内和体外由免疫复合物信号传导的骨髓衍生 DC 产生的增强 Th2 反应中的作用。在此目的中，我们建议研究以下假设：BMDC 产生的 IL-33 直接或间接诱导增强的 Th2 反应。目标 #2：确定先天免疫细胞是否通过体内 Fc?R 信号传导产生 IL-33。在此目的中，我们建议研究以下假设：内源性 TLR4 激活的呼吸道 DC 上的 Fc?R 信号传导诱导 IL-33 产生，进而增强 Th2 介导的炎症。我们的研究将对我们理解 IgG 对 DC 功能的调节及其如何影响 Th2 介导的疾病产生重大影响。此外，我们将获得对 DC 介导的 T 细胞分化调节机制的宝贵见解，并有可能确定临床治疗的新靶点。在我们的实验室，我们拥有成功分析体内 Th2 介导的气道炎症的专业知识，以及完成本提案目标的所有必要资源和工具。此外，我们还做出了一项创新发现，即次级反应中 DC 的激活和基因调控可能会受到抗原特异性 IgG 的存在的影响。 公共卫生相关性：哮喘和过敏症影响着全球约 6 亿人，是基础科学造福于临床医学的一项重要挑战。儿童是哮喘患者的主要群体，而且还在不断增长。我们的研究调查了过度免疫反应导致哮喘和过敏的机制。