Role Of Surfactant In Innate and Adaptive Immunity

描述（由申请人提供）：肺上皮是人体与环境之间最大的界面之一，每天暴露在大约11000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抗原，而对有害病原体作出适当反应。肺表面活性物质是局部宿主防御系统的一种。最近的研究已经确定了两种表面活性剂蛋白，SP-A和SP-D，作为胶原样凝集素集合家族的成员，在宿主防御中起作用。在本提案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，以协调最大限度地防御吸入过敏原和病原体，同时最大限度地减少过度活跃免疫反应的潜在有害炎症后果。我们发现SP-A和SP-D具有细胞特异性作用，表明它们以特定的方式调节细胞反应。我们建议实现三个具体目标。目的1将定义SP-A和SP-D及其受体在调节骨髓来源树突状细胞和肥大细胞的抗原摄取、细胞内靶向和抗原呈递中的作用。阻断抗体和无受体小鼠将用于验证树突状细胞和肥大细胞特异性反应由不同的收集受体调节的假设，这些受体将病原体靶向到不同的细胞内加工途径，通过MHCI和MHCII呈现。目的2将明确SP-A抑制树突状细胞成熟的机制。研究将用分离细胞、抗受体阻断抗体和来自受体和细胞因子缺失小鼠的细胞进行，以验证SP-A与特定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将研究SP-A和SP-D介导的II型上皮细胞和肺树突状细胞免疫功能在正常和炎症肺中的调节。研究将采用体外分离细胞和体内收集小鼠两种肺炎症模型，LPS模型和卵清蛋白过敏性炎症模型。这些研究将为SP-A和SP-D在调节和协调先天免疫系统和适应性免疫系统细胞功能中的作用提供新的信息，有助于我们理解SP-A和SP-D在炎症性肺部疾病中的作用，并有助于开发新的表面活性剂治疗方法。

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.