Surfactant-Protein Innate Immunity in an Asthma Model

描述(由申请人提供)：先天免疫系统的组成部分在调节过敏反应方面很重要。表面活性蛋白(SP)-D是一种在肺组织中结构性表达的胶原样凝集素，通过帮助清除吸入性病原体，在天然宿主防御中发挥着重要作用。我们的初步研究表明，在过敏性呼吸道炎症中，该分子的表达显著增加。此外，SP-D还显示出对Th2型淋巴细胞活化的强烈抑制作用，提示在过敏性呼吸道改变的发生发展中具有特定的作用。该方案的假设表明，SP-D通过在三个不同的水平上抑制变应原诱导的事件来保护肺粘膜表面：(I)。肺泡巨噬细胞(MP)在远端空气中结构性分泌的SP-D有助于清除过敏原，以防止产生生产性T细胞反应。(Ii)。SP-D可促进树突状细胞(DC)的迁移，促进对淋巴结的免疫反应的区隔。(三)。Th2型免疫反应增强SP-D的合成，进而抑制T细胞的进一步激活，提供负反馈调节环路。用烟曲霉菌提取物(Af)致敏小鼠，研究SP-D缺乏和重组SP-D治疗的效果。在目标1中，SP-D的作用将被定义为MPS在体外清除Af颗粒以及在Af诱导的SP-D-/-和SP-D+/+小鼠体内变态反应性炎症中的作用。目的#2将在过敏原暴露模型中利用荧光标记的DC来描述SP-D是否在促进DC迁移到淋巴结中起重要作用。目的#3将评估SP-D对变应原诱导的T细胞活化和随后的Th2型免疫反应的直接抑制作用。在目标#4中，将通过描绘细胞类型和涉及的调节途径来研究Th2型细胞因子对SP-D合成的调节。这些研究的结果将扩大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，并定义先天免疫系统和获得性免疫系统之间的新联系。SP-D治疗干预变态反应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.