Dendritic cells in allergic pulmonary inflammation

树突状细胞在过敏性肺部炎症中的作用

• 批准号: 6565033
• 负责人: Mary Fisher Lipscomb
• 金额: $ 27.93万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-01-05 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565033
• 关键词: T cell receptor; antiinflammatory agents; asthma; biopsy; cell cell interaction; cell migration; corticosteroids; cytokine; dendritic cells; diagnostic respiratory lavage; eosinophil; genetically modified animals; helper T lymphocyte; human subject; immunoglobulin E; immunopathology; inflammation; laboratory mouse; leukocyte activation /transformation; ovalbumin; passive immunization; patient oriented research; respiratory hypersensitivity; tissue /cell culture

(Applicant's Abstract) Allergic asthma is a chronic inflammatory disease in which an inappropriate Th2 immune response plays a dominant role. Antigen presenting cells, particularly lung dendritic cells (DCs), are essential for the initiation and expression of pulmonary immunity by T cells. The capacity of DCs to stimulate T cells to become Th1 or Th2 cells in a primary immune response is strongly influenced by other cells and their secreted products in the immediate vicinity, i.e., microenvironment, of the DCs. Respiratory pathogens have been associated with either an increased or decreased risk for the development of asthma. We speculate that this altered asthma risk may relate to the capacity of the infectious agent to create a lung microenvironment that influences DCs to mature into either Th1 promoting or Th2 promoting DCs. Furthermore, once Th2 mediated lung inflammation is established, we speculate DC numbers increase and DC function is enhanced to perpetuate the response. We propose three aims to address the role of lung DCs in the primary and secondary immune responses of allergic asthma using both murine models and samples from people with asthma. Aim 1 will test the hypothesis that active pulmonary inflammation at the time of initial exposure to allergen influences lung DCs to mature to either Th1-promoting (type 1) or Th2-promoting (type 2) DCs. In Aim 2, we will test the hypothesis that lung DCs isolated from lungs undergoing allergic inflammation are influenced by their microenvironment to become the most potent resident antigen presenting cells for re-stimulating specific Th2 cells. To accomplish this aim, we will compare lung DCs, macrophages, B cells and IgE-armed mast cells in stimulating clonal Th2 cells to produce enhanced allergic inflammation and airway hyperreactivity. In aim 3, we will test the hypothesis that Th2 mediated inflammation in the lungs of asthmatic individuals induces the recruitment, maturation and commitment of peripheral blood monocytes into DCs with the capacity to initiate and elicit potent Th2 responses. We will use three approaches to test this hypothesis, one using murine bone marrow-derived cells inoculated into mice with allergic inflammation, one assessing the effect of bronchoalveolar lavage fluids from asthmatics on human peripheral blood monocytes and monocyte-derived DCs, and one enumerating immature and mature lung DCs in bronchial biopsies from asthmatics and controls and also asthmatics before and after anti IgE therapy. The overall goal is to understand how lung DCs regulate lung immunity to cause asthma, with the hope of devising strategies to prevent and treat chronic immune-mediated pulmonary inflammation.

（申请人摘要）过敏性哮喘是一种慢性炎症性疾病