Dendritic cells in allergic pulmonary inflammation

过敏性哮喘是一种慢性炎症性疾病， 其中不适当的Th 2免疫应答起主导作用。抗原 呈递细胞，特别是肺树突状细胞（DC），对于 T细胞启动和表达肺免疫。的能力 在初次免疫中刺激T细胞成为Th 1或Th 2细胞 反应强烈影响其他细胞及其分泌的产品， 直接邻近，即，微环境，DC。呼吸 病原体与增加或减少的风险有关， 哮喘的发展。我们推测，这种改变的哮喘风险可能 与感染原创造肺部的能力有关 微环境影响DC成熟为Th 1促进或 Th 2促进DC。此外，一旦Th 2介导的肺部炎症发生， 我们推测DC数量增加，DC功能增强， 让答案永久化。我们提出了三个目标来解决肺DC的作用， 在过敏性哮喘的原发性和继发性免疫反应中， 小鼠模型和哮喘患者的样本。目标1将测试 假设初次接触时存在活动性肺部炎症 过敏原影响肺DC成熟为Th 1促进型（1型）或 Th 2-促进（2型）DC。在目标2中，我们将检验肺 从经历过敏性炎症的肺中分离的DC受到以下因素的影响： 它们的微环境成为最有效的常驻抗原呈递 用于再刺激特定Th 2细胞的细胞。为达致这个目标，我们会 比较肺树突状细胞、巨噬细胞、B细胞和IgE武装的肥大细胞在刺激 克隆Th 2细胞产生增强的过敏性炎症和气道 反应过度在目标3中，我们将检验Th 2介导的 哮喘个体肺部的炎症诱导募集， 外周血单核细胞成熟并定型为DC， 启动和引发有效Th 2应答的能力。我们将使用三个 检验这一假设的方法之一是使用小鼠骨髓来源的细胞， 接种到患有过敏性炎症的小鼠中， 支气管肺泡灌洗液对人外周血的影响 单核细胞和单核细胞衍生的DC，以及一个计数未成熟和成熟的DC， 在哮喘患者和对照组的支气管活检中， 抗IgE治疗前后的哮喘患者。总体目标是 了解肺DCs如何调节肺免疫导致哮喘， 制定策略来预防和治疗慢性免疫介导的肺 炎症

(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.