Dendritic cells and IgE in asthma

描述：哮喘是一种呼吸道疾病，其特征是一种独特的慢性炎症，与辅助性T淋巴细胞的Th2亚群产生的一系列细胞因子有关。哮喘最常与特应性、过敏原致敏和免疫球蛋白E反应有关，这些反应也受Th2细胞因子的调节。利用节段性变应原攻击(SAC)的人类模型，已证实嗜酸性粒细胞、嗜碱性粒细胞和辅助/记忆T淋巴细胞的特异性募集，提示细胞募集的高度选择性机制。我们新的初步数据表明，树突状细胞(DC)在SAC部位迅速聚集，数量足以检查其功能。这项建议将研究树突状细胞在过敏原的炎症和免疫反应中的作用。我们将检验这一假设，即在过敏反应早期，DC通过直接募集或通过与循环单核细胞前体分化而在肺内积聚。通过改变抗原提呈细胞(APC)功能的平衡，肺树突状细胞(DC)在定位炎症部位的免疫反应中起着关键作用。我们的方法如下：1)我们将检测髓系和浆细胞样树突状细胞向肺内募集的动力学，并确定参与肺内树突状细胞募集的趋化因子。2)使用纯化的DC亚群和CD4+T细胞，我们将对肺树突状细胞进行功能研究，以确定与肺内募集相关的ARC功能和DC细胞因子产生的变化。3)检测炎症过程中肺树突状细胞高亲和力IgE受体(Fcc.RI)的表达，探讨其在DC功能中的作用。 体外研究将检测用非激活、抗LGE(Omalizumab)和其他刺激物调节IgE对DC功能的影响。更好地了解DC的募集、功能和IgE的作用，可能会为旨在恢复与过敏性哮喘相关的呼吸道免疫反应失调的平衡的策略提供洞察。

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.