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: 6365341
• 负责人: JO RAE WRIGHT
• 金额: $ 34.65万
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6365341
• 关键词: allergens; antigen presentation; calcium flux; cell cell interaction; cytokine; dendritic cells; gene targeting; genetically modified animals; human tissue; immunity; inflammation; laboratory mouse; leukocyte activation /transformation; lung disorder; molecular pathology; opsonin; protein structure function; pulmonary surfactants; respiratory function; respiratory hypersensitivity; tissue /cell culture

DESCRIPTION (provided by applicant): Although pulmonary surfactant has been traditionally viewed as a surface tension reducing substance, recent studies demonstrate that it also functions in host defense. Two surfactant proteins, SP-A and SP-D, arc members of a family of innate immune proteins known as collectins that bind pathogens and facilitate the clearance by immune cells. SF-A and SP-D also regulate a variety of immune cell functions. The hypothesis to be tested in this proposal is that SP-A and SP-D interact with cells of both the adapative and innate immune systems to coordinately maximize defense against inhaled particles and pathogens while minimizing potentially harmful inflammatory consequences. We propose that SF-A and SP-D enhance uptake and presentation of antigens by dendritic cells, as they passes through the airspace in response to an inflammatory challenge, and that SF-A and SP-D suppress lymphocyte activation while they are in the alveolar and airway compartments, thereby minimizing damage to the delicate pulmonary epithelium that could occur in the lymphocytes were constantly activated in the airspaces. These effects would maximize the ability of dendritic cells to present antigen once they migrate to the lymph nodes and encounter lymphocytes that are no longer suppressed by SP-A or SP-D. This model is consistent with previous observations that lung lymphocytes are hyporesponsive compared to circulating lymphocytes and with our preliminary data showing that SP-A an SP-D inhibit lymphocyte proliferation and enhance antigen presentation by dendritic cells. The hypothesis will be tested by investigating 4 specific aims. Aim 1 is to determine if SP-A and SP-t enhance antigen uptake and presentation by dendritic cells. Aim 2 is to determine if SP-A and SP-D affect production of regulatory molecules (cytokines, cell surface receptors, and co-stimulatory molecules) b) dendritic cells stimulated with either antigen or LPS. Aim 3 is to investigate the mechanism by which SP-A and SP-D regulate lymphocyte activation. Aim 4 is to define the role of SP-A and SP-D in the pathogenesis o inflammatory lung disease in vivo using SF-A and SP-D deficient mice. These studies will provide information about the role of SF-A and SP-D in regulating the functions of two important cells of the adaptive about immune system and contribute to our understanding of the role of SF-A and SP-D inflammatory lung diseases.

描述（由申请人提供）：尽管肺表面活性剂已有 传统上被视为降低表面张力的物质，最近的研究 证明它还在主机防御中起作用。两个表面活性剂蛋白， SP-A和SP-D，一个先天免疫蛋白家族的ARC成员称为 结合病原体并促进免疫细胞清除的集合蛋白。 SF-A和SP-D还调节多种免疫细胞功能。假设 在此提案中进行测试是SP-A和SP-D都与两者的细胞相互作用 适应性和先天免疫系统，以协调最大化防御 针对吸入颗粒和病原体，同时最大程度地减少潜在有害 炎症后果。我们建议SF-A和SP-D增强摄取，并 抗原通过树突细胞通过 空域应对炎症挑战，而SF-A和SP-D 淋巴细胞在肺泡和气道中抑制淋巴细胞激活 隔室，从而最大程度地减少对细腻肺上皮的损害 这可能发生在淋巴细胞中，在空体中不断激活。 这些影响将最大化树突状细胞呈现抗原的能力 一旦它们迁移到淋巴结并遇到无 SP-A或SP-D抑制更长的时间。该模型与以前的 观察到肺淋巴细胞与循环相比是反应不足的 淋巴细胞和我们的初步数据表明SP-A sp-d抑制 淋巴细胞增殖并增强树突状细胞的抗原表现。 该假设将通过研究4个具体目标来检验。目标1是 确定SP-A和SP-T是否增强了树突状的抗原吸收和表现 细胞。 AIM 2是确定SP-A和SP-D是否影响调节的产生 分子（细胞因子，细胞表面受体和共刺激分子）b） 用抗原或LP刺激的树突状细胞。目标3是调查 SP-A和SP-D调节淋巴细胞激活的机制。目标4是 定义SP-A和SP-D在发病机理中的作用o炎症肺 使用SF-A和SP-D缺乏小鼠在体内疾病。这些研究将提供 SF-A和SP-D在调节两个功能中的作用的信息 适应性的有关免疫系统的重要细胞，并有助于我们 了解SF-A和SP-D炎性肺疾病的作用。