Surfactant-Protein Innate Immunity in an Asthma Model

描述（由申请方提供）：先天免疫系统的组分在调节过敏性致敏中很重要。表面活性蛋白（SP）-D，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先天性宿主防御中起着重要作用。我们的初步研究表明，这种分子在过敏性气道炎症中的表达显著增加。此外，SP-D显示出对Th 2型淋巴细胞活化的强抑制作用，表明在过敏性气道变化的发展中具有特异性功能。该建议的假设指出，SP-D通过在三个不同水平抑制变应原诱导的事件来保护肺粘膜表面：（I）。远端空气空间中组成性分泌的SP-D有助于肺泡巨噬细胞（MP）清除过敏原，以防止产生生产性T细胞应答。（二）. SP-D增强树突状细胞（DC）迁移，以促进淋巴结免疫反应的区室化。（三）。Th 2型免疫应答增强SP-D合成，这反过来又抑制进一步的T细胞活化，提供负反馈调节回路。将使用烟曲霉（Af）提取物在已建立的模型中致敏小鼠，并研究SP-D缺乏和重组SP-D治疗的效果。在目标#1中，SP-D的作用将在体外MP对Af颗粒的清除中以及在体内SP-D-/-和SP-D+/+小鼠的Af诱导的过敏性炎症中定义。目的#2将描述在过敏原暴露模型中，使用荧光标记的DC，SP-D在促进DC迁移至淋巴结中是否重要。目的#3将评估SP-D对变应原诱导的T细胞活化和随后的Th 2型免疫应答的直接抑制作用。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Th 2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导的哮喘发病机制中的意义的理解，并定义先天性和适应性免疫系统之间的新联系。SP-D治疗干扰过敏性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.