Mechanisms of Pulmonary Mast Cell Recruitment and Maturation

肺肥大细胞招募和成熟的机制

• 批准号: 8303348
• 负责人: Michael Fagersten Gurish
• 金额: $ 39.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303348
• 关键词: Adjuvant; Adoptive Cell Transfers; Allergens; Allergic; Allergic inflammation; Antibodies; Antigens; Appearance; Asthma; Backcrossings; Biopsy; Bone Marrow; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Characteristics; Cytoprotection; Development; Effector Cell; Employee Strikes; Epithelium; Generations; Genetic; Goals; Health; Helminths; Homing; Human; Hyperplasia; Hypersensitivity; In Situ; Individual; Infection; Inflammation; Integrins; Interleukin-10; Interleukin-3; Interleukin-4; Interleukin-9; Interleukins; Intestines; Knockout Mice; Lead; Lung; Lung diseases; Lymphoid Cell; Mature Lymphocyte; Mediating; Mediator of activation protein; Mouse Strains; Mucous Membrane; Mus; Nude Mice; Organ; Ovalbumin; Pathogenesis; Pathology; Pathway interactions; Phase; Play; Population; Process; Protocols documentation; Regulatory T-Lymphocyte; Role; Small Intestines; Source; T-Lymphocyte; TNF gene; Testing; Th1 Cells; Th2 Cells; Time; Tissues; Tracheobronchial; Transcript; Treatment Efficacy; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; autocrine; base; cell type; cysteinyl leukotriene receptor; cysteinyl leukotriene receptor 2; cysteinyl-leukotriene; cytokine; human TNFRSF1A protein; intraepithelial; leukotriene-C4 synthase; mast cell; mastocytosis; migration; mouse model; novel therapeutics; progenitor; receptor; reconstitution; response; tumor necrosis factor alpha receptor; Adjuvant; Adoptive Cell Transfers; Allergens; Allergic; Allergic inflammation; Antibodies; Antigens; Appearance; Asthma; Backcrossings; Biopsy; Bone Marrow; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Characteristics; Cytoprotection; Development; Effector Cell; Employee Strikes; Epithelium; Generations; Genetic; Goals; Health; Helminths; Homing; Human; Hyperplasia; Hypersensitivity; In Situ; Individual; Infection; Inflammation; Integrins; Interleukin-10; Interleukin-3; Interleukin-4; Interleukin-9; Interleukins; Intestines; Knockout Mice; Lead; Lung; Lung diseases; Lymphoid Cell; Mature Lymphocyte; Mediating; Mediator of activation protein; Mouse Strains; Mucous Membrane; Mus; Nude Mice; Organ; Ovalbumin; Pathogenesis; Pathology; Pathway interactions; Phase; Play; Population; Process; Protocols documentation; Regulatory T-Lymphocyte; Role; Small Intestines; Source; T-Lymphocyte; TNF gene; Testing; Th1 Cells; Th2 Cells; Time; Tissues; Tracheobronchial; Transcript; Treatment Efficacy; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; autocrine; base; cell type; cysteinyl leukotriene receptor; cysteinyl leukotriene receptor 2; cysteinyl-leukotriene; cytokine; human TNFRSF1A protein; intraepithelial; leukotriene-C4 synthase; mast cell; mastocytosis; migration; mouse model; novel therapeutics; progenitor; receptor; reconstitution; response; tumor necrosis factor alpha receptor

DESCRIPTION (provided by applicant): Mast cells (MCs) are important effector cells in type 1 hypersensitivity and asthma as indicated by the efficacy of treatments directed to the MC and its mediators. Bronchial biopsies from asthmatic individuals contain substantially more MCs than do biopsies from nonasthmatic controls yet essentially nothing is known about the mechanisms responsible for this increase. The overall goal of this project is to further characterize the pathways that regulate the recruitment, maturation, survival, and expansion of MC populations in pulmonary tissues with allergic inflammation using mouse models. Although MCs and MC progenitors (MCp) are sparse in mouse lung at baseline, the appearance of mature MCs in tracheobronchial epithelium (intraepithelial (IE) MC hyperplasia) is a characteristic of allergic, T-cell dependent inflammation. We find a rapid increase in the number of MCp in the allergen-challenged lung that depends on CD4+ cells and the cytokines interleukin (IL)-9 and tumor necrosis factor alpha (TNFa) although not on Th1 or Th2 cells. Using antibody-mediated depletion, null mice, and selective reconstitution, this project will test the hypotheses that: 1. IL-9 (through proliferation and cytoprotection) and TNFa (through induction of VCAM-1) are necessary for the early accumulation of MCp in the allergen-challenged lung, and; 2. IL-9 is provided by Th17 cells. Further, as the number of IE MC increases at time when MCp numbers have returned to baseline, we suspect that the development of the IE MC hyperplasia depends on Th2-derived cytokines and cysteinyl leukotrienes (based on analyses of mice lacking leukotriene C4 synthase (LTC4S)). The second aim of this project then will test the hypotheses that: 3. The accumulation of pulmonary MCp is a necessary prerequisite for the development of tracheobronchial IE MC hyperplasia and; 4. IE MC hyperplasia in the tracheobronchial mucosa requires cytokines derived from Th2 cells (IL-3, IL-10, IL-4, and possibly IL-9) that facilitate the in situ proliferation and maturation of MCp and that cys-LTs can act as secondary messengers in these processes. Thus, this project will define the pathways and mechanisms involved in the appearance of the pulmonary MC implicated in the pathogenesis of allergic pulmonary diseases. PUBLIC HEALTH RELEVANCE: The appearance of a pulmonary mast cell hyperplasia is characteristic of allergic inflammation in this organ. The immunological and developmental pathways leading to this increase in the number of pulmonary mast cells will be further defined in this project which in turn should lead to novel therapeutic possibilities for the amelioration of mast cell mediated pathologies in the lung.

描述（由申请人提供）：肥大细胞（MCS）是1型高敏性和哮喘中重要的效应细胞，如针对MC及其介体的处理功效所表明的。来自哮喘患者的支气管活检所包含的MC比非心脏控制的活检要多得多，但基本上对导致这种增加的机制却一无所知。该项目的总体目标是进一步表征调节使用小鼠模型过敏性炎症的肺组织中MC种群募集，成熟，存活和扩张的途径。尽管MCS和MC祖细胞（MCP）在基线时小鼠肺中稀疏，但在气管上上皮（上皮内（IE）MC增生）中成熟MC的出现是过敏性，T细胞依赖性炎症的特征。我们发现依赖于CD4+细胞的过敏原挑战性肺中的MCP数量迅速增加，而细胞因子白介素（IL）-9和肿瘤坏死因子α（TNFA），尽管不是TH1或TH2细胞。使用抗体介导的耗竭，无效的小鼠和选择性重建，该项目将测试：1。IL-9（通过增殖和细胞保护）和TNFA（通过诱导VCAM-1）（通过VCAM-1）（通过VCAM-1）进行MCP早期在过敏蛋白挑战者促进蛋白的肺和； 2。IL-9由Th17细胞提供。此外，随着MCP数量返回基线时IE MC的数量增加，我们怀疑IE MC增生的发展取决于Th2衍生的细胞因子和Cysteinyl Leukotrienes（基于缺乏白细胞三烯C4合成酶（LTC4S）的小鼠的分析）。然后，该项目的第二个目的将检验以下假设：3。肺MCP的积累是开发气管bronchial IE MC增生的必要先决条件。 4。气管支气管粘膜中的MC增生需要源自Th2细胞（IL-3，IL-10，IL-4和可能的IL-9）的细胞因子，以促进MCP的原位增殖和成熟，并且Cys-LT可以作为这些过程中的二次汇报。因此，该项目将定义与过敏性肺部疾病发病机理有关的肺MC出现的途径和机制。公共卫生相关性：肺肥大细胞增生的出现是该器官过敏性炎症的特征。该项目将进一步定义导致肺肥大细胞数量增加的免疫学和发育途径，这反过来又将导致肺中肥大细胞介导的病理学改善的新型治疗可能性。