Surfactant-Protein Innate Immunity in an Asthma Model

哮喘模型中的表面活性剂蛋白先天免疫

• 批准号: 7022277
• 负责人: ANGELA HACZKU
• 金额: $ 34.82万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022277
• 关键词: Aspergillus; airborne allergen; alveolar macrophages; asthma; cell migration; cellular immunity; collagen; cytokine; dendritic cells; disease /disorder model; enzyme linked immunosorbent assay; genetically modified animals; helper T lymphocyte; host organism interaction; hypersensitivity; immunocytochemistry; in situ hybridization; inflammation; laboratory mouse; laboratory rat; lectin; leukocyte activation /transformation; lymph nodes; protein biosynthesis; pulmonary surfactants

DESCRIPTION (provided by applicant): Components of the innate immune system are important in regulation of allergic sensitization. Surfactant protein (SP)-D, a constitutively expressed collagen-like lectin in the lung, plays a prominent role in innate host defense by aiding clearance of inhaled pathogens. Our preliminary studies demonstrated a significantly increased expression of this molecule in allergic airway inflammation. Further, SP-D has shown strong inhibitory effects on Th2-type lymphocyte activation suggesting a specific function in development of allergic airway changes. The hypothesis of this proposal states that SP-D protects lung mucosal surfaces by inhibiting allergen-induced events at three different levels: (I). Constitutively secreted SP-D in the distal air spaces aids clearance of allergens by alveolar macrophages (MP) to prevent development of a productive T cell response. (II). SP-D enhances dendritic cell (DC) migration to promote compartmentalization of the immune response to the lymph nodes. (III). Th2-type immune response enhances SP-D synthesis, which in turn inhibits further T cell activation, providing a negative feedback regulatory loop. Aspergillus fumigatus (Af) extract will be used to sensitize mice in an established model and the effects of SP-D deficiency and recombinant SP-D treatment will be studied. In Aim #1 the role of SP-D will be defined in clearance of Af particles by MPs in vitro and in Af-induced allergic inflammation of SP-D-/- and SP-D+/+ mice in vivo. Aim #2 will delineate whether SP-D is important in promoting DC migration to the lymph nodes using fluorescently labeled DCs in an allergen exposure model. Aim #3 will assess the direct inhibitory effects of SP-D on allergen-induced T cell activation and the ensuing Th2-type immune response. In Aim #4 the Th2-type cytokine induced regulation of SP-D synthesis will be investigated by delineating the cell types and regulatory pathways involved. Results from these studies will extend our understanding of the implications of this pattern recognition molecule in the pathogenesis of fungal-allergen induced asthma, and define a novel connection between the innate and adaptive immune system. The potential opportunity to interfere with allergic sensitization by SP-D treatment bears high clinical significance.

描述（由申请人提供）：先天免疫系统的组成部分对于过敏性致敏的调节很重要。表面活性蛋白 (SP)-D 是一种在肺中组成型表达的胶原样凝集素，通过帮助清除吸入的病原体，在宿主先天防御中发挥着重要作用。我们的初步研究表明，该分子在过敏性气道炎症中的表达显着增加。此外，SP-D 对 Th2 型淋巴细胞活化显示出强烈的抑制作用，表明其在过敏性气道变化的发展中具有特定功能。该提案的假设指出，SP-D 通过在三个不同水平抑制过敏原诱导的事件来保护肺粘膜表面：(I)。远端空气空间中持续分泌的 SP-D 有助于肺泡巨噬细胞 (MP) 清除过敏原，从而防止产生高效 T 细胞反应。 （二）。 SP-D 增强树突状细胞 (DC) 迁移，以促进对淋巴结的免疫反应的区室化。 （三）。 Th2 型免疫反应增强 SP-D 合成，进而抑制 T 细胞进一步激活，提供负反馈调节回路。烟曲霉 (Af) 提取物将用于在已建立的模型中使小鼠致敏，并将研究 SP-D 缺乏和重组 SP-D 治疗的影响。在目标 #1 中，SP-D 的作用将被定义为体外 MP 清除 Af 颗粒以及体内 SP-D-/- 和 SP-D+/+ 小鼠 Af 诱导的过敏性炎症。目标 #2 将描述在过敏原暴露模型中使用荧光标记的 DC，SP-D 对于促进 DC 迁移至淋巴结是否重要。目标 #3 将评估 SP-D 对过敏原诱导的 T 细胞激活和随后的 Th2 型免疫反应的直接抑制作用。在目标 4 中，将通过描述所涉及的细胞类型和调节途径来研究 Th2 型细胞因子诱导的 SP-D 合成调节。这些研究的结果将扩展我们对这种模式识别分子在真菌过敏原诱发的哮喘发病机制中的影响的理解，并定义先天性免疫系统和适应性免疫系统之间的新联系。 SP-D 治疗干扰过敏致敏的潜在机会具有很高的临床意义。