Dendritic cells and IgE in asthma

描述：哮喘是一种气道疾病，其特征是一种独特形式的慢性炎症，与辅助性T淋巴细胞th2亚群产生的细胞因子谱相关。哮喘通常与特应性、过敏原致敏和IgE反应有关，这些反应也受Th2细胞因子的调节。利用人类节段性过敏原攻击（SAC）模型，嗜酸性粒细胞、嗜碱性粒细胞和辅助/记忆T淋巴细胞的特异性募集已被证实，表明细胞募集的高度选择性机制。我们的新初步数据表明，树突状细胞（dc）迅速积聚在SAC的位置，其数量足以允许检查其功能。本提案将检查树突状细胞在炎症和免疫反应过敏原的作用。我们将检验在过敏反应早期，dc通过直接募集或从循环单核细胞前体分化在肺中积累的假设。通过改变抗原呈递细胞（APC）功能的平衡，肺dc在炎症部位的免疫应答定位中发挥关键作用。我们的方法如下：1)我们将检查髓细胞和浆细胞样DC向肺募集的动力学，并确定参与肺DC募集的趋化因子。2)使用纯化的DC亚群和CD4+ T细胞，我们将对肺DC进行功能研究，以确定ARC功能的变化和DC细胞因子的产生与肺募集相关。3)我们将评估炎症期间高亲和力IgE受体（Fcc.RI）在肺DC中的表达，并探讨IgE介导的DC功能机制。

DESCRIPTION: Asthma is an airways disease characterized by a unique form of chronic inflammation associated with a profile of cytokines produced by the Th2-subset of helper T lymphocytes. Asthma is most often associated with atopy, allergen sensitization, and the IgE response, which are also regulated by Th2 cytokines. Using the human model of segmental allergen challenge (SAC), specific recruitment of eosinophils, basophils, and helper/memory T lymphocytes has been demonstrated, suggesting highly selective mechanisms of cellular recruitment. Our novel preliminary data indicates that dendritic cells (DCs) rapidly accumulate at sites of SAC in numbers sufficient to allow examination of their function. This proposal will examine the role of dendritic cells in the inflammatory and immunologic response to allergen. We will examine the hypothesis that early in the allergic response, DCs accumulate in the lung by direct recruitment or by differentiation from circulating monocyte precursors. By altering the balance of antigen presenting cell (APC) function, lung DCs play a critical role in localizing immune responses to the inflammatory site. Our approaches are as follows 1) We will examine the kinetics of myeloid and plasmacytoid DC recruitment to the lung, and identify the chemokines involved in lung DC recruitment. 2) Using purified DC subsets and CD4+ T cells, we will perform functional studies of lung DCs to define changes in ARC functions and DC cytokine production associated with recruitment to the lung. 3) We will evaluate the expression of high affinity IgE receptor (Fcc.RI) on lung DCs during inflammation, and explore the role of IgE-mediated mechanisms on DC function. In vitro studies will examine the effect on DC function of modulating IgE with a non-activating, anti-lgE (omalizumab) and other stimuli. Better understanding of DC recruitment, function, and the role of IgE may provide insight into strategies aimed at restoring balance to the dysregulated immune response in the airways associated with allergic asthma.