Leukocyte Activating Fc Receptors in Immune Lung Injury

免疫性肺损伤中的白细胞激活 Fc 受体

• 批准号: 6528176
• 负责人: Alan D Schreiber
• 金额: $ 35.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528176
• 关键词: alveolar macrophages; antibody receptor; cell line; gene targeting; genetically modified animals; human tissue; immune complex; immunoglobulin G; immunopathology; immunoregulation; laboratory mouse; lung injury; neutrophil; transfection

DESCRIPTION (provided by applicant): Leukocytes such as polymorphonuclear leukocytes (PMN) and macrophages, play an important role both in immune complex disease and in host defense. Macrophages and PMN express on their surface Fcgamma receptors (FcgammaR) which 1) interact with IgG containing immune complexes to produce tissue damage, but 2) also function to clear IgG coated bacteria in host defense. In the lung, Fc receptors and, importantly, the individual Fc receptors have been little studied. We will employ transgenic mice and mice deficient in specific FcR in a combined in vitro and in vivo molecular and cell biology approach to elucidate the role of individual Fc receptors in an animal model of immune lung injury. Both human and mouse macrophages express the activating FcgammaRs FcgammaRI and FcgammaRIIIA which interact with a FcR gamma subunit. We have determined that FcgammaRI is unique among FcR not only in the ability to bind monomeric IgG, but also to signal through both its alpha and gamma subunits. Human macrophages and PMN also express the potent activating FcR FcgammaRIIA, which is absent in mice and does not interact with the y chain. We now have available FcgammaRIIA transgenic (TG) mice, which we have determined express FcgammaRIIA on the macrophage surface to a similar extent as humans and have enhanced clearance of IgG coated cells. Our novel mouse strains include: 1) mice individually lacking either FcgammaRI, FcgammaRIIIA or the gamma chain and 2) mice TG for human FcgammaRIIA (as well as FcgammaRIIA crosses) developed with the participation of our laboratory. Our hypothesis, suggested by our data, is that in the lung FcgammaRI plays a predominant role in the release of inflammatory mediators, while FcgammaRIIA plays a predominant role in host defense. Elucidating the role(s) of specific leukocyte FcgammaRs in the lung is potentially important for developing strategies for effective therapy. Another goal is to define the molecular mechanisms involved in specific mediator release induced by individual lung macrophage FcR, specifically FcgammaRI. We have determined that the cytoplasmic domain (CY) of the FcgammaRI alpha chain is required for release of macrophage IL-6. We will examine structure/function relationships of FcgammaRI involved in signaling for IL-6 release. Human FcgammaRI and chimeras of human FcgammaRI, containing transmembrane domains which cannot associate with endogenous murine Fcgamma receptors, will be transfected into a murine macrophage cell line. Our hypothesis is that specific sequences in the FcgammaRI alpha chain CY, but not the gamma chain, are required for IL-6 release.

描述（由申请人提供）： 白细胞，例如多形核白细胞（PMN）和巨噬细胞，播放 在免疫复杂疾病和宿主防御中的重要作用。 巨噬细胞和PMN在其表面FCGAMMA受体（FCGAMMAR）上表达 1）与含有免疫复合物的IgG相互作用以产生组织 损坏，但2）还起作用可在宿主防御中清除IgG涂层细菌。在 肺，FC受体以及重要的是，单个FC受体已经是 小研究。我们将采用特异性的转基因小鼠和小鼠 FCR在体外和体内分子和细胞生物学方法中 阐明单个FC受体在免疫动物模型中的作用 肺部受伤。人和小鼠巨噬细胞都表达激活 FCGAMMARS FCGAMMARI和FCGAMMARIIIA与FCR伽马亚基相互作用。 我们已经确定Fcgammari在FCR中不仅在能力方面是独一无二的 结合单体IgG，但也通过其α和伽玛发出信号 亚基。人类巨噬细胞和PMN也表达有效的激活FCR fcgammariia，小鼠不存在，与Y链不相互作用。 现在，我们有fcgammariia transnic（TG）小鼠，我们拥有 确定巨噬细胞表面上的表达fcmamariia在相似的程度上 作为人类，并增强了对IgG涂层细胞的清除。我们的新颖鼠标 菌株包括：1）小鼠单独缺乏fcgammari，fcgammariiia 或伽马链和2）小鼠TG用于人类fcgammariia（以及 Fcgammariia crosses）随着我们实验室的参与而发展。我们的 我们的数据提出的假设是，在肺fcgammari中发挥了A 在炎症介质的释放中主要作用，而fcgammariia 在宿主防御中起主要作用。阐明特定的作用 肺中的白细胞FCAMMAR对于发育可能很重要 有效治疗的策略。另一个目标是定义分子 由单个肺诱导的特定介质释放的机制 巨噬细胞FCR，特别是fcgammari。我们已经确定 释放需要Fcgammariα链的细胞质结构域（CY） 巨噬细胞IL-6。我们将检查的结构/功能关系 FCGAMMARI参与IL-6释放的信号传导。人fcgammari和 人fcgammari的嵌合体，包含跨膜结构域 与内源性鼠FCGAMMA受体结合，将转染到A 鼠巨噬细胞系。我们的假设是 IL-6需要Fcgammari alpha链CY，但不是伽马链 发布。