Cellular Basis of Hypersensitivity Diseases in Humans

人类过敏性疾病的细胞基础

• 批准号: 6858780
• 负责人: KARL FRANK AUSTEN
• 金额: $ 115.39万
• 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/6858780
• 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)：这个协作和协同计划项目的中心焦点是肥大细胞(MC)的发育生物学和功能，以及半胱氨酰白三烯生成途径的调节和功能，现在与先天性和获得性免疫炎症交叉。正在进行的方法是通过研究培养来源的人单核细胞(HMCS)的配体，对参与过敏/哮喘炎症效应通路的表达或功能的关键蛋白的定向干扰的小鼠进行研究，以及通过比较哮喘捐赠者的细胞和来自正常个体的细胞来观察失调反应的能力。白细胞免疫球蛋白样受体(LIR)家族由激活LIR7和抑制LIR3的嗜碱性粒细胞、嗜酸性粒细胞、中性粒细胞和MC祖细胞(MCP)组成。激活LIR7的连接释放预形成的介体半胱氨酰白三烯(CysLTs)和嗜酸性粒细胞的细胞因子，同时LIR3在嗜碱性粒细胞上连接可阻止这一反应。因此，项目1寻求在慢性哮喘患者的特定效应细胞的表达和功能水平上对这一先天途径进行失调。认识到溶血磷脂酸(LPA)在其生理浓度下，在谱系导向的细胞因子存在的情况下，不仅可以替代血清，而且可以推动脐血祖细胞的增殖和成熟，使其成为构成表型，这揭示了血管周围MC可能存在的动态平衡信号，具有基于炎症的放大作用。人类和小鼠之间识别的三个LPA受体(LPAR)的高度同源性表明，可以在项目2中的LPA1R缺失品系中初步评估靶向干扰的小鼠品系中研究该配体对皮肤和肺部的影响。在项目3中，LTC4合成酶(LTC4S)和半胱氨基白三烯1受体(CysLT1R)缺失品系的产生，正在开发中的CysLT2R缺失品系，以及一个转人LTC4S基因的品系允许在急性和慢性免疫性肺损伤模型中评估cysLT途径的产物。在培养的HMCs中观察到的IL-4对LTC4S的诱导可以在小鼠MCs中复制，这一发现允许使用零菌株来分析调节信号。MCP的跨内皮细胞运动和迁移对于其组织分布、成熟和表型表达是必不可少的，需要(_4J37和CXCR2)才能归巢到肠道，而不是肺。在项目4中，气溶胶抗原诱导的肺部和肠道炎症的模型将再次使用无效菌株和阻断单抗来揭示每个器官中MCP池扩大所需的共同或独特的途径。综上所述，这些研究将为竞争LIR对效应或细胞功能的紧张性控制、血清LPA对MC表型的先天调节、MC LTC4S基因的调控表达以及MCP的组织特异性归巢和募集以进行分布和表型成熟提供新的信息。