Surfactant-Protein Innate Immunity in an Asthma Model

描述（由申请人提供）：先天免疫系统的成分在过敏致敏的调节中很重要。表面活性蛋白(SP)-D是一种在肺中组成性表达的胶原样凝集素，通过帮助清除吸入病原体在先天宿主防御中发挥重要作用。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著增加。此外，SP-D对th2型淋巴细胞活化有很强的抑制作用，提示在过敏性气道改变的发展中具有特定的功能。本提案的假设表明，SP-D通过在三个不同水平上抑制过敏原诱导的事件来保护肺粘膜表面：(1)。在远端空气中组成性分泌的SP-D有助于肺泡巨噬细胞（MP）清除过敏原，以防止产生T细胞反应。(二)。SP-D增强树突状细胞（DC）迁移，促进对淋巴结的免疫反应区隔化。(3)。th2型免疫反应增强SP-D合成，进而抑制T细胞进一步活化，提供负反馈调节回路。利用烟曲霉（Aspergillus fumigatus, Af）提取物致敏小鼠模型，研究SP-D缺乏症和重组SP-D治疗的效果。在Aim #1中，SP-D的作用将被定义为体外MPs清除Af颗粒，以及体内SP-D-/-和sp - +/+小鼠Af诱导的过敏性炎症。Aim #2将在过敏原暴露模型中使用荧光标记的DC来描述SP-D在促进DC向淋巴结迁移中是否重要。目的3将评估SP-D对过敏原诱导的T细胞活化和随后的th2型免疫反应的直接抑制作用。在Aim #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哮喘发病机制中的意义的理解，并定义先天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。

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.