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）：哮喘和过敏影响全球约6亿人，是基础科学造福临床医学的重要挑战。我们目前对这些疾病的了解表明Th2细胞在炎症反应中起主要作用。然而，诱导T细胞向Th2表型分化的因素仍然是这些疾病中尚未解决的重要问题之一。在哮喘和过敏性疾病的发病机制中，IgE的作用是确定的，但抗原特异性IgG也大量存在于这些个体的血清中。我们之前已经发现了IgG激活受体Fc？iii，在小鼠模型中调节th2依赖性炎症。我们的发现，先前的致敏，导致抗原特异性IgG，可以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。以前，人们认为抗原提呈细胞在原发性和继发性反应中对TLR激动剂等刺激的反应相似。然而，我们的研究结果现在表明，当抗原摄取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，包括上调IL-33细胞因子的产生。我们的总体假设是抗原特异性IgG交联Fc？R增加th2免疫反应，部分是通过DC产生IL-33。我们提出以下具体目标：目的1：确定IL-33在体外和体内免疫复合物信号骨髓源性DC产生的增强Th2反应中的作用。在这一目的中，我们提出了一个假设，即BMDCs产生IL-33，直接或间接地诱导Th2反应增强。目的2：确定IL-33是否由先天免疫细胞通过Fc产生？体内的R信号。在这篇论文中，我们建议研究Fc？内源性TLR4激活的呼吸dc上的R信号诱导IL-33的产生，从而增加th2介导的炎症。我们的研究将对我们理解IgG对DC功能的调节以及它如何影响th2介导的疾病产生重大影响。此外，我们将对dc介导的T细胞分化的调节机制获得有价值的见解，并有可能在临床中确定新的治疗靶点。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，我们有一个创新的发现，DC激活和二次反应中的基因调控可能受到抗原特异性IgG存在的影响。