Role Of Surfactant In Innate and Adaptive Immunity

描述（由申请人提供）：肺上皮是身体与环境之间最大的界面之一，每天暴露于约11，000升被细菌、病毒、病原体和过敏原污染的空气中。肺宿主防御系统必须忽略无害的抗原，但对有害的病原体作出适当的反应。肺表面活性物质是宿主局部防御系统之一。最近的研究已经确定了两种表面活性剂蛋白，SP-A和SP-D，作为胶原样凝集素家族的成员，其在宿主防御中起作用。在该提议中要测试的总体假设是SP-A和SP-D与适应性和先天免疫系统的细胞相互作用，以协调地最大化对吸入的过敏原和病原体的防御，同时最小化过度旺盛的免疫应答的潜在有害炎症后果。我们的研究结果表明，SP-A和SP-D具有细胞特异性效应，表明它们以特定的方式调节细胞反应。我们建议追求三个具体目标。目的1明确SP-A和SP-D及其受体在调节骨髓来源的树突状细胞和肥大细胞对抗原的摄取、细胞内靶向和抗原提呈中的作用。将使用阻断抗体和受体缺失小鼠来检验树突细胞和肥大细胞特异性应答由不同的聚集蛋白受体调节的假设，所述聚集蛋白受体将病原体靶向不同的细胞内加工途径，以通过MHCI和MHCII呈递。目的二是明确SP-A抑制树突状细胞成熟的机制。将使用分离的细胞、抗受体阻断抗体以及来自受体和细胞因子无效小鼠的细胞进行研究，以检验SP-A与特异性受体相互作用以改变抑制树突状细胞成熟的细胞因子或细胞因子受体的产生的假设。目的3研究SP-A和SP-D对正常肺和炎症肺Ⅱ型上皮细胞和树突状细胞免疫功能的调节作用。将使用两种肺部炎症模型，LPS模型和过敏性炎症的卵清蛋白模型，用分离的细胞进行体外研究，并用胶原聚集蛋白缺失小鼠进行体内研究。这些研究将提供有关SP-A和SP-D在调节和协调先天性和适应性免疫系统细胞功能中的作用的新信息，并有助于我们理解SP-A和SP-D在炎症性肺部疾病中的作用，以及开发新的含表面活性剂的治疗方法。

DESCRIPTION (provided by applicant): 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.