Role Of Surfactant In Innate and Adaptive Immunity

肺上皮是人体与环境之间最大的界面之一， 它每天暴露在大约11,000升被细菌、病毒、 病原体和过敏原。肺宿主防御系统必须忽略无害的抗原，但 对有害病原体做出适当的反应。局部宿主防御系统之一是肺脏 表面活性剂。最近的研究已经确定了两个表面活性蛋白，SP-A和SP-D是成员 属于胶原样凝集素家族，具有宿主防御功能。总体假设是 实验结果表明，SP-A和SP-D既能与适应性细胞相互作用，又能与天然细胞相互作用 免疫系统协调最大限度地防御吸入过敏原和病原体，同时 将过度活跃的免疫反应的潜在有害炎症后果降至最低。 我们的研究发现，SP-A和SP-D具有细胞特异性效应，这表明它们调节细胞 以特定于上下文的方式进行响应。我们建议追求三个具体目标。目标1将定义 SP-A和SP-D及其受体在调节抗原摄取、细胞内靶向、 以及骨髓来源的树突状细胞和肥大细胞的抗原提呈。封闭抗体 受体缺失的小鼠将被用来检验树突状细胞和肥大细胞特异性 针对不同细胞内病原体的不同的集合素受体调节反应。 通过MHCI和MHCII呈现的处理路径。目标2将定义 SP-A抑制树突状细胞的成熟。研究将用分离的细胞进行， 抗受体阻断抗体，并用来自受体和细胞因子缺失的小鼠的细胞测试 SP-A与特定受体相互作用改变细胞因子或细胞因子产生的假说 抑制树突状细胞成熟的受体。AIM 3将研究SP-A和SP-D介导的 正常人和正常人肺树突状细胞和II型上皮细胞免疫功能的调节 肺部发炎。研究将在体外用分离的细胞进行，并在体内用集合素缺失的小鼠进行 采用两种肺部炎症模型，内毒素模型和卵白蛋白过敏模型。 发炎。这些研究将提供有关SP-A和SP-D在 调节和协调先天和获得性免疫系统细胞的功能 有助于我们理解SP-A和SP-D在炎症性肺部疾病中的作用 含表面活性物质的新型疗法的开发。

The epithelium of the lung is one of the largest interfaces between the body and the environment and it is exposed daily to approximately 11,000 liters of air that is contaminated with bacteria, viruses, pathogens and allergens. The pulmonary host defense system must ignore harmless antigens but respond appropriately to harmful pathogens. One of local host defense system is pulmonary surfactant. Recent studies have identified two of the surfactant proteins, SP-A and SP-D, as members of the collectin family of collagen-like lectins that function in host defense. The overall hypothesis to be tested in this proposal is that SP-A and SP-D interact with cells of both the adaptive and innate immune systems to coordinately maximize defense against inhaled allergens and pathogens while minimizing potentially harmful inflammatory consequences of an over exuberant immune response. Our findings that SP-A and SP-D have cell specific effects suggest that they modulate cellular response in a context specific manner. We propose to pursue three specific aims. Aim 1 will define the roles of SP-A and SP-D and their receptors in regulating antigen uptake, intracellular targeting, and antigen presentation by bone marrow derived dendritic cells and mast cells. Blocking antibodies and receptor null mice will be used to test the hypothesis that dendritic and mast cell specific responses are modulated by different collectin receptors that target pathogens to different intracellular processing pathways for presentation via MHCI and MHCII. Aim 2 will define the mechanism by which SP-A inhibits the maturation of dendritic cells. Studies will be performed with isolated cells, anti-receptor blocking antibodies, and with cells from receptor and cytokine null mice to test the hypothesis that SP-A interacts with specific receptors to alter production of cytokines or cytokine receptors that inhibit dendritic cell maturation. Aim 3 will investigate SP-A and SP-D mediated regulation of Type II epithelial cell and lung dendritic cell immune functions in the normal and inflamed lung. Studies will be conducted in vitro with isolated cells and in vivo with collectin null mice using two models of lung inflammation, the LPS model and the ovalbumin model of allergic inflammation. These studies will provide new information about the role of SP-A and SP-D in regulating and coordinating the functions of cells of the innate and adaptive immune system and contribute to our understanding of the role of SP-A and SP-D in inflammatory lung diseases and to development of novel surfactant-containing therapies.