Innate and Adaptive Immune Signaling in Asthma

描述(由申请人提供)： AADCRC应用的总体目标是了解先天性和获得性免疫信号如何对哮喘的发病机制做出贡献，从而为这种情况开发新的治疗策略。我们特别强调抗病毒和过敏反应的启动和终止是哮喘的关键因素，我们使用高保真的分离细胞和小鼠模型将我们的发现直接转化为人类。因此，AADRC由三个相互关联的项目组成，这三个项目涉及：第一，哮喘是如何在呼吸道上皮细胞的天然免疫反应水平上启动的(项目1)，第二，这些天然信号如何随后通过补体系统成分与T调节(Treg)细胞相互作用而触发抑制性免疫反应(项目2)，以及第三，适应性免疫系统中的额外抑制信号如何最终关闭免疫和炎症过程(项目3)。因此，项目1专注于呼吸道上皮细胞如何实现干扰素驱动的STAT1信号的适当平衡，以实现最佳的抗病毒防御，从而防止哮喘特征的急性和慢性发展。该项目通过在转基因小鼠中设计STAT1信号的缺乏和高反应性来实验测试这一建议，然后使用相同的生物标记物来研究病毒感染儿童哮喘发展过程中的这种平衡。项目2使用相同的病毒性毛细支气管炎小鼠模型和过敏原攻击来确定补体系统的特定成分如何有助于先天性反应，而其他成分为抑制抗病毒和过敏反应的Treg细胞的发育提供信号。项目3延续了免疫平衡的主题，并提出关闭免疫反应的缺陷可能会导致对过敏和其他刺激的过度和长期的炎症反应。本项目利用其在其他类似受体(PD-1)和相应配体的背景下发现的新的抑制性受体(BTLA)来确定这些抑制信号对小鼠过敏反应的影响。反过来，每个项目(1、2和3)将使用成年哮喘患者的样本来验证和扩展其发现。重叠的科学目标创建了一个可以得到一组共同核心支持的协同方案：行政核心将协调AADCRC的活动，并将提供计算机和统计支持。人类学科核心将招募儿童和成人作为研究对象，获得临床研究材料，并确保临床方案的一致性。形态核心提供组织处理和分析。Mouse Core开发了新的转基因小鼠，并为呼吸道功能的生理测量提供了设施。项目和核心互动基于一个总体原则，即每个项目都是从在分离细胞和小鼠模型中建立分子假说开始的，并将这些模型的发现转化为对患有哮喘的儿童和成人的研究。

DESCRIPTION (provided by applicant): The overall goal of this AADCRC application is to understand how innate and adaptive immune signals contribute to the pathogenesis of asthma and thereby develop new therapeutic strategies for this condition. We give special emphasis to the initiation and termination of both antiviral and allergic responses as critical elements in asthma, and we use isolated cell and mouse models with high fidelity to directly translate our findings to humans. The AADRC therefore consists of three interrelated Projects that address first, how the asthmatic condition may be initiated at the level of the innate immune response in the airway epithelium (Project 1), second, how these innate signals may subsequently trigger an inhibitory immune response via complement system components interacting with T regulatory (Treg) cells (Project 2), and third, how additional inhibitory signals in the adaptive immune system may ultimately shut off the immune and inflammatory process (Project 3). Thus, Project 1 focuses on how airway epithelial cells achieve a proper balance of IFN-driven Stat1 signals to achieve optimal antiviral defense and so prevent the acute and chronic development of asthma traits. The Project tests this proposal experimentally by engineering deficiency versus hyper-responsiveness of Stat1 signaling in transgenic mice, and then uses the same biomarkers to study this balance during the development of asthma in children with viral infection. Project 2 uses the same mouse model of viral bronchiolitis as well as allergen challenge to determine how specific components of the complement system may contribute to the innate response while other components provide a signal for the development of Treg cells that dampen the antiviral and allergic responses. Project 3 continues the theme for immune balance and the proposition that a deficiency in turning off the immune response could lead to an excessive and prolonged inflammatory response to allergic and other stimuli. This Project takes advantage of its discovery of a new inhibitory receptor (BTLA) in the context of other similar receptors (PD-1) and corresponding ligands to define the influence of these inhibitory signals on the allergic response in mice. In turn, each Project (1, 2, and 3) will validate and extend its findings using samples from adult patients with established asthma. Overlapping scientific goals create a synergistic program that can be supported by a common set of cores: the Administrative Core will coordinate the activities of the AADCRC and will provide computer and statistical support. The Human Subjects Core will recruit children and adults as research subjects, obtain clinical research materials, and assure uniformity among clinical protocols. The Morphology Core provides for tissue processing and analysis. The Mouse Core develops new transgenic mice and provides facilities for physiologic measurements of airway function. Project and Core interactions are based on the overall principle that each Project begins with molecular hypothesis building in isolated-cell and mouse models and translates findings from these models to studies of children and adults with asthma.