Cellular Basis of Hypersensitivity Diseases in Humans

人类过敏性疾病的细胞基础

• 批准号: 6681185
• 负责人: KARL FRANK AUSTEN
• 金额: $ 57.75万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681185
• 关键词: clinical research; hypersensitivity; inflammation; leukotrienes; mast cell

DESCRIPTION (provided by applicant): The central focus of this collaborative and synergic program project directed to the developmental biology and function of the mast cell (MC) and the regulation and function of the cysteinyl leukotriene-generating pathway now intersects with both innate and adaptive immune inflammation. The ongoing approach is broadened by studies of ligands for culture-derived human MCs (hMCs), of mice with targeted disruptions of the key proteins involved in expression or function of the effector pathways of allergic/asthmatic inflammation, and by a capacity to compare cells from asthmatic donors with those from normal individuals to see dysregulated responses. The leukocyte immunoglobulin-like receptor (LIR) family is represented by an activating LIR7 and an inhibitory LIR3 on basophils, eosinophils, neutrophils, and MC progenitors (MCp). Coligation to activate LIR7 releases preformed mediators, cysteinyl leukotrienes (cysLTs), and cytokines from eosinophils and simultaneous coligation of LIR3 on basophils prevent this response. Thus, Project 1 seeks dysregulation of this innate pathway at the expression and function levels for particular effector cells of patients with chronic asthma. The recognition that lysophosphatidic acid (LPA) at its physiologic concentration in the presence of lineage-directed cytokines not only replaces serum, but also drives proliferation and maturation of cord blood progenitors into a constitutive phenotype reveals a possible homeostatic signal for the perivascular MC with potential for inflammation-based amplification. The high homology of the three recognized LPA receptors (LPARs) between human and mouse suggests that the ligand can be studied for cutaneous and pulmonary effects in the mouse strains with targeted disruptions initially assessed in the LPA1R null strain in Project 2. In Project 3, the generation of LTC4 synthase (LTC4S) and cysteinyl leukotriene 1 receptor (CysLT1R) null strains, the CysLT2R null strain under development, and a strain transgenic for the human LTC4S gene allows assessment of the cysLT pathway products in models of acute and chronic immunologic pulmonary injury. The finding that IL-4 induction of LTC4S observed with culture-derived hMCs can be replicated with mouse MCs allows dissection of the regulatory signals using null strains. The transendothelial movement and migration of MCp essential to their tissue-based distribution, maturation, and phenotypic expression requires (_4J37 and CXCR2 for homing to intestine but not lung. In Project 4, a model of aerosol antigen-induced pulmonary and intestinal inflammation will again use null strains and blocking mAbs to reveal the common or unique pathways required for expansion of the MCp pool in each organ. Taken together, these studies will provide new information on the tonic control of effect or cell functions by competing LIRs, on the innate regulation of the MC phenotype by serum LPA, on the regulated expression of the MC LTC4S gene, and on the tissue-specific homing and recruitment of MCp for distribution and phenotypic maturation.

描述（由申请人提供）：这个协作和协同项目的中心重点是肥大细胞（MC）的发育生物学和功能，以及半胱氨酸白三烯生成途径的调节和功能，现在与先天和适应性免疫炎症交叉。目前正在进行的方法是通过对培养来源的人MCs （hMCs）配体的研究，对靶向破坏过敏/哮喘炎症效应通路表达或功能的关键蛋白的小鼠，以及将哮喘供体细胞与正常人供体细胞进行比较以观察失调反应的能力进行扩展。白细胞免疫球蛋白样受体（LIR）家族由活化LIR7和抑制LIR3代表，LIR3作用于嗜碱性粒细胞、嗜酸性粒细胞、中性粒细胞和MC祖细胞（MCp）。连接激活LIR7释放预形成的介质，半胱氨酸白三烯（cysLTs）和来自嗜酸性粒细胞的细胞因子，同时连接LIR3在嗜碱性细胞上阻止这种反应。因此，项目1在慢性哮喘患者的特定效应细胞的表达和功能水平上寻找这种先天途径的失调。在谱系导向细胞因子存在的情况下，溶血磷脂酸（LPA）的生理浓度不仅可以取代血清，还可以驱动脐带血祖细胞的增殖和成熟，形成一种组成型表型，这一认识揭示了血管周围MC可能存在的稳态信号，具有炎症放大的潜力。人类和小鼠之间三种被识别的LPA受体（LPARs）的高度同源性表明，该配体可以研究小鼠菌株的皮肤和肺部作用，项目2中最初在LPA1R无效菌株中评估了靶向干扰。在项目3中，LTC4合成酶（LTC4S）和半胱氨酸白三烯1受体（CysLT1R）无效菌株的产生，正在开发的CysLT2R无效菌株，以及转人LTC4S基因的菌株，可以评估急性和慢性免疫性肺损伤模型中的cysLT途径产物。IL-4诱导LTC4S的发现可以在小鼠MCs中复制，从而可以使用零菌株解剖调节信号。MCp的跨内皮运动和迁移对其基于组织的分布、成熟和表型表达至关重要，需要(_4J37和CXCR2归巢到肠道而不是肺。在项目4中，气溶胶抗原诱导的肺部和肠道炎症模型将再次使用零菌株和阻断单抗来揭示每个器官中MCp池扩展所需的共同或独特途径。综上所述，这些研究将为以下方面提供新的信息：竞争性lir对效果或细胞功能的补益控制，血清LPA对MC表型的先天调节，MC LTC4S基因的调控表达，以及MCp在组织特异性归巢和募集中的分布和表型成熟。