Role Of Surfactant In Innate and Adaptive Immunity

表面活性剂在先天性和适应性免疫中的作用

• 批准号: 7790613
• 负责人: JO RAE WRIGHT
• 金额: $ 38.02万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7790613
• 关键词: Air; Allergens; Allergic inflammation; Alveolar; Alveolar Macrophages; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Bacteria; Blocking Antibodies; Bone Marrow; Breathing; Cell Maturation; Cell physiology; Cells; Collagen; Collectins; Cytokine Receptors; Dendritic Cells; Development; Effector Cell; Environment; Epithelial Cells; Epithelium; Family; Fc Receptor; Figs - dietary; Funding; Germ Lines; Host Defense; Immune; Immune response; Immune system; Immunity; In Vitro; Inflammatory; Inflammatory Response; Irritants; Knockout Mice; Lectin; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Major Histocompatibility Complex; Mediating; Modeling; Muramidase; Opsonin; Ovalbumin; Pathway interactions; Phagocytes; Phagocytosis; Play; Process; Production; Protein Family; Proteins; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Receptor Cell; Regulation; Research Personnel; Role; Sterility; Surface; Surface Tension; System; T-Cell Activation; T-Lymphocyte; Testing; Time; Type II Epithelial Receptor Cell; Virus; adaptive immunity; cytokine; immune function; in vivo; mast cell; member; neutrophil; novel; particle; pathogen; programs; receptor; response; surfactant; uptake

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.

肺上皮是身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。肺部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反应。局部宿主防御系统之一是肺 表面活性剂。最近的研究已经确定了两种表面活性蛋白 SP-A 和 SP-D 作为成员 属于胶原蛋白样凝集素的集合素家族，具有宿主防御功能。总体假设为 该提案中测试的是 SP-A 和 SP-D 与适应性细胞和先天性细胞相互作用 免疫系统协调最大程度地防御吸入过敏原和病原体，同时 最大限度地减少过度旺盛的免疫反应造成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，表明它们调节细胞 以特定于上下文的方式响应。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呈递。封闭抗体 和受体缺失小鼠将用于测试树突状细胞和肥大细胞特异性的假设 反应由不同的集合素受体调节，这些受体将病原体靶向不同的细胞内 通过 MHCI 和 MHCII 呈现的处理路径。目标 2 将定义机制 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小鼠的细胞来测试 SP-A 与特定受体相互作用以改变细胞因子或细胞因子的产生的假设 抑制树突状细胞成熟的受体。目标 3 将研究 SP-A 和 SP-D 介导的 正常和正常状态下 II 型上皮细胞和肺树突状细胞免疫功能的调节 肺部发炎。将使用分离的细胞进行体外研究，并使用集合素无效小鼠进行体内研究 使用两种肺部炎症模型：LPS模型和过敏性卵清蛋白模型 炎。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的功能 有助于我们了解 SP-A 和 SP-D 在炎症性肺部疾病中的作用，并 开发新型含表面活性剂的疗法。

项目成果

Pulmonary surfactant proteins A and D directly suppress CD3+/CD4+ cell function: evidence for two shared mechanisms.

肺表面活性蛋白 A 和 D 直接抑制 CD3 /CD4 细胞功能：两种共享机制的证据。

• 发表时间: 2002-11-15
• 作者: Borron, Paul J;Mostaghel, Elahe A;Doyle, Carolyn;Walsh, Eric S;McHeyzer;Wright, Jo Rae
• 通讯作者: Wright, Jo Rae

Review: Collectins link innate and adaptive immunity in allergic airway disease.

评论：集合素将先天免疫和适应性免疫与过敏性气道疾病联系起来。

• 发表时间: 2010-06
• 影响因子: 3.2
• 作者: Ledford, Julie G;Pastva, Amy M;Wright, Jo Rae
• 通讯作者: Wright, Jo Rae

Lung effector memory and activated CD4+ T cells display enhanced proliferation in surfactant protein A-deficient mice during allergen-mediated inflammation.

在过敏原介导的炎症过程中，表面活性蛋白 A 缺陷小鼠的肺效应记忆和激活的 CD4 T 细胞显示出增强的增殖。

• 发表时间: 2011-03-01
• 作者: Pastva, Amy M;Mukherjee, Sambuddho;Giamberardino, Charles;Hsia, Bethany;Lo, Bernice;Sempowski, Gregory D;Wright, Jo Rae
• 通讯作者: Wright, Jo Rae

Surfactant protein D increases phagocytosis and aggregation of pollen-allergen starch granules.

表面活性蛋白 D 增加花粉过敏原淀粉颗粒的吞噬作用和聚集。

• 发表时间: 2005-04
• 作者: Erpenbeck, Veit J;Malherbe, Delphine C;Sommer, Stefanie;Schmiedl, Andreas;Steinhilber, Wolfram;Ghio, Andrew J;Krug, Norbert;Wright, Jo Rae;Hohlfeld, Jens M
• 通讯作者: Hohlfeld, Jens M

Alveolar epithelial type II cells induce T cell tolerance to specific antigen.

肺泡上皮 II 型细胞诱导 T 细胞对特定抗原的耐受。

• 发表时间: 2008-01-15
• 作者: Lo, Bernice;Hansen, Soren;Evans, Kathy;Heath, John K;Wright, Jo Rae
• 通讯作者: Wright, Jo Rae