Specificity and mechanisms of lung lymphocyte homing

肺淋巴细胞归巢的特异性和机制

• 批准号: 7922028
• 负责人: Linh Phuong Nguyen
• 金额: $ 5.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922028
• 关键词: Adhesions; Adult; Affect; Antibodies; Antigens; Asthma; Back; Biochemical; Biological Assay; Biological Models; Blocking Antibodies; Blood; Bronchus-Associated Lymphoid Tissue; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cell Line; Cells; Chemotactic Factors; Child; Chronic; Colon; Disease; Environment; Flow Cytometry; Gene Expression; Goals; Home environment; Homeostasis; Homing; Immune System Diseases; Immune response; Immunohistochemistry; Inflammatory; Knock-out; Ligands; Lung; Lymphocyte; Lymphoid Tissue; Mediating; Memory; Mesentery; Migration Assay; Modeling; Molecular; Molecular Profiling; Mus; Organ; Orphan; Pathway interactions; Pattern; Peptides; Peripheral; Phenotype; Physiological; Play; Pneumonia; Proteins; Publishing; Recruitment Activity; Research; Research Proposals; Role; Site; Skin; Source; Specificity; Spleen; Stream; System; T memory cell; T-Cell Activation; T-Lymphocyte; Techniques; Testing; Tissues; Transgenic Model; Western World; adhesion receptor; airway inflammation; base; cell type; chemokine; cytokine; fMet-Leu-Phe receptor; in vivo; inhibitor/antagonist; knockout animal; knockout gene; lymph nodes; migration; mouse model; mutant; novel; novel therapeutics; receptor; response; selective expression; trafficking

DESCRIPTION (provided by applicant): Asthma affects approximately 20% of children and 5% of adults in the western world. Marked by chronic inflammation of the airway tract, asthma is mediated by pro-inflammatory proteins, including cytokines, chemokines and adhesion molecules. Inhibitors of trafficking molecules are emerging as new therapeutic avenues for the treatment of immune diseases. Clarifying the mechanism of T cell homing to the lung and the role of lung lymphocyte-expressed receptors could delineate potential targets for the treatment of asthma and other pulmonary inflammatory diseases. This proposal aims to test whether a specific mechanism of pulmonary lymphocyte homing to lung exists and to identify the adhesion and chemoattractant receptors involved. On the basis of published studies, a mechanism of lung-selective migration of lymphocytes has been implicated. However, whether the pathway for pulmonary T cell homing to the lung is specific and distinct from skin- or gut-homing is not known. Using mouse models and in vivo migration assays that we have developed, we will first formally test whether pulmonary memory T cells preferentially migrate back to the lung, as compared with the lung- and other tissue-homing of cells from other systemic organs and lymphoid tissues. In addition, by applying established immunohistochemistry techniques, we will identify the micro-environment or compartments of the lung to which the homed cells localize. Second, to determine the molecular players involved, we will use flow cytometry and blocking antibodies in in vivo migration assays to test the involvement of specifc endothelial and lymphocyte adhesion receptors. Chemoattractant receptors are known to regulate the migration of lymphocytes from the blood stream to sites of immune responses. Our preliminary gene expression analyses consistently identified the lung-selective expression of two putative chemoattractant receptors. Using mouse models of gene knockout and wildtype controls, we will lastly determine the expression profile of these receptors on ymphocyte subpopulations. Importantly, to understand whether these novel receptors play a role in lung homing, we will also test how the deficiency of these receptors in the knockout animals affect the lung homing of pulmonary lymphocytes. Relevance: The goal of this research proposal is to determine whether lung homing is selective and to elucidate the underlying mechanisms. Information gained from this research can be applied towards developing inhibitors of the contributing proteins for the treatment of asthma or other lung inflammatory diseases.

描述（由申请人提供）：哮喘影响西方世界约20%的儿童和5%的成人。哮喘以气道慢性炎症为标志，由促炎蛋白介导，包括细胞因子、趋化因子和粘附分子。运输分子的抑制剂正在成为治疗免疫疾病的新的治疗途径。阐明T细胞归巢肺的机制和肺淋巴细胞表达受体的作用可以为哮喘和其他肺部炎症性疾病的治疗提供潜在的靶点。本研究的目的是检测肺淋巴细胞归巢的特异性机制是否存在，并确定其中涉及的粘附和趋化因子受体。根据已发表的研究，淋巴细胞的肺选择性迁移机制已被提及。然而，肺T细胞归巢到肺的途径是否是特异性的并且不同于皮肤或肠道归巢尚不清楚。使用我们已经开发的小鼠模型和体内迁移试验，我们将首先正式测试与来自其他全身器官和淋巴组织的细胞的肺和其他组织归巢相比，肺记忆T细胞是否优先迁移回肺。此外，通过应用已建立的免疫组织化学技术，我们将确定归巢细胞所在的肺的微环境或隔室。其次，为了确定参与的分子，我们将在体内迁移试验中使用流式细胞术和阻断抗体来检测特异性内皮细胞和淋巴细胞粘附受体的参与。已知化学引诱剂受体可以调节淋巴细胞从血流迁移到免疫反应部位。我们的初步基因表达分析一致地确定了两个假定的趋化因子受体的肺选择性表达。使用基因敲除和野生型对照的小鼠模型，我们将最终确定这些受体在淋巴细胞亚群上的表达谱。重要的是，为了了解这些新的受体是否在肺归巢中发挥作用，我们还将测试敲除动物中这些受体的缺乏如何影响肺淋巴细胞的肺归巢。相关性：这项研究计划的目的是确定肺归巢是否具有选择性，并阐明其潜在机制。从这项研究中获得的信息可以应用于开发用于治疗哮喘或其他肺部炎症性疾病的贡献蛋白质的抑制剂。