Role of Surfactant in Innate and Adaptive Immunity

描述(申请人提供)：虽然肺表面活性物质已被 传统上被视为降低表面张力的物质，最近的研究 证明它在宿主防御中也起作用。两种表面活性蛋白质， SP-A和SP-D是天然免疫蛋白家族的成员，该家族被称为 与病原体结合并促进免疫细胞清除的集合素。 SF-A和SP-D还调节多种免疫细胞功能。假说 在本方案中要测试的是SP-A和SP-D与两者的细胞相互作用 适应性和先天免疫系统协调最大限度地防御 防止吸入颗粒物和病原体，同时最大限度地减少潜在的危害 炎症性后果。我们认为SF-A和SP-D促进摄取和 树突状细胞的抗原提呈，当它们通过 应对煽动性挑战的空域，以及SF-A和SP-D 抑制淋巴细胞在肺泡和呼吸道的激活 隔室，从而将对脆弱的肺上皮的损害降至最低 这可能发生在淋巴细胞中，在空气中不断被激活。 这些效应将最大限度地提高树突状细胞呈递抗原的能力 一旦它们迁移到淋巴结并遇到非淋巴细胞 不再由SP-A或SP-D抑制。这个模型与以前的模型是一致的 肺淋巴细胞与循环相比反应迟钝的观察 淋巴细胞和我们的初步数据显示SP-A和SP-D具有抑制作用 淋巴细胞的增殖和增强树突状细胞的抗原提呈。 这一假设将通过调查4个具体目标来检验。目标1是 确定SP-A和SP-t是否促进树突状细胞对抗原的摄取和提呈 细胞。目的2是确定SP-A和SP-D是否影响调节性基因的产生 分子(细胞因子、细胞表面受体和共刺激分子)b) 抗原或脂多糖刺激树突状细胞。目标3是调查 SP-A和SP-D调节淋巴细胞活化的机制。目标4是 SP-A、SP-D在炎性肺病发病机制中的作用 利用SF-A和SP-D缺陷小鼠体内致病。这些研究将提供 关于SF-A和SP-D在调节两种细胞功能中的作用的信息 关于免疫系统的适应性的重要细胞和贡献我们的 了解SF-A和SP-D在炎症性肺病中的作用。

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.