Role of Surfactant in Innate and Adaptive Immunity

描述（由申请人提供）：虽然肺表面活性物质已被 传统上被视为表面张力降低物质，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， SP-A和SP-D是先天性免疫蛋白家族的成员，称为 结合病原体并促进免疫细胞清除的凝集素。 SF-A和SP-D还调节多种免疫细胞功能。的假设 在这个提议中要测试的是SP-A和SP-D与两者的细胞相互作用， 适应性和先天性免疫系统协调最大化防御 防止吸入颗粒物和病原体，同时最大限度地减少潜在有害物质 炎性后果。我们认为SF-A和SP-D增强了摄取， 树突状细胞在通过淋巴细胞时呈递抗原， 空中应对煽动性挑战，SF-A和SP-D 抑制淋巴细胞在肺泡和气道中的活化 隔室，从而最大限度地减少对脆弱的肺上皮细胞的损伤 淋巴细胞中可能发生的变化在空气中不断被激活。 这些效应将使树突状细胞呈递抗原的能力最大化 一旦它们迁移到淋巴结并遇到淋巴细胞， SP-A或SP-D抑制的时间更长。这一模式与此前 观察到肺淋巴细胞与循环淋巴细胞相比 我们的初步数据显示SP-A和SP-D抑制了 淋巴细胞增殖和增强树突状细胞的抗原呈递。 将通过调查4个具体目标来检验假设。目标1： 确定SP-A和SP-t是否增强树突状细胞的抗原摄取和呈递， 细胞目的2是确定SP-A和SP-D是否影响调节因子的产生。 分子（细胞因子、细胞表面受体和共刺激分子）B） 用抗原或LPS刺激的树突状细胞。目标3：调查 SP-A和SP-D调节淋巴细胞活化的机制。目标4是 探讨SP-A和SP-D在炎症性肺损伤发病机制中的作用 使用SF-A和SP-D缺陷型小鼠进行的体内疾病研究。这些研究将提供 关于SF-A和SP-D在调节两种功能中的作用的信息， 重要细胞的适应性免疫系统，并有助于我们的 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.