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The role of plasmacytoid dendritic cells in allergic asthma

浆细胞样树突状细胞在过敏性哮喘中的作用

基本信息

批准号：
219588867
负责人：
Dr. Kai Bratke
金额：
--
依托单位：
Zentrum für Innere Medizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/219588867?language=en
关键词：
role plasmacytoid dendritic cells allergic

项目摘要

To develop novel, more effective therapeutic strategies for the treatment of allergic asthma an improved understanding of allergen-mediated lung inflammation is needed. Recently, we identified plasmacytoid dendritic cells (pDCs) as a possible target population. In the first period of this project these pDCs were phenotypically and functionally characterized. The most important results were an increased expression of FcεRIα on peripheral blood pDCs from atopic asthmatics compared with healthy controls and an increased expression of this IgE receptor chain on endobronchial pDCs following allergen provocation. In addition, we showed for the first time the expression of IL-4 by pDCs which was upregulated in pDCs differentiated in a Th2-like cytokine milieu. These results lead to the hypothesis that in allergic asthma pDCs may function as effector cells which support or even amplify allergic inflammation. This new project is supposed to focus on this hypothesis. Therefore, the effects of crosslinking of the high affinity IgE receptor on different maturation states of pDCs will be investigated. First, naïve peripheral blood pDCs from healthy controls and allergic asthmatics will be extensively compared on mRNA, protein as well as on functional levels. To analyse more differentiated pDCs an established in vitro model will be used where IL-3 is added to naïve pDCs in the presence of a Th2-like cytokine milieu to generate so called Th2-pDCs. To analyse the in vivo relevance of this data the established human asthma model of segmental allergen challenge will be employed. Endobronchial pDCs which have been differentiated in a Th2-milieu in vivo will be isolated from bronchoalveolar lavage after allergen challenge and then will be further analysed following FcεRI-crosslinking. We expect these data will enable us to make a clear statement whether pDCs function as effector cells or as immune regulatory cells in allergic asthma. Finally, in view of the development of novel therapeutic strategies we want to identify factors whose neutralisation, inhibition or addition will increase the tolerogenic potential of Th2-pDCs and decrease their Th2-effector potential. For this attempt the in vitro model of Th2-pDCs will be performed.

为了开发新的，更有效的治疗过敏性哮喘的治疗策略，需要更好地了解过敏原介导的肺部炎症。最近，我们确定浆细胞样树突状细胞（pDC）作为一个可能的目标群体。在该项目的第一阶段，这些pDC的表型和功能特征。最重要的结果是与健康对照相比，特应性哮喘患者外周血pDC上FcεRIα的表达增加，过敏原激发后支气管内pDC上IgE受体链的表达增加。此外，我们首次显示了IL-4在pDC中的表达，其在Th 2样细胞因子环境中分化的pDC中上调。这些结果导致了这样的假设，即在过敏性哮喘中，pDC可能作为效应细胞起作用，其支持甚至放大过敏性炎症。这个新项目应该关注这个假设。因此，将研究高亲和力IgE受体的交联对pDC的不同成熟状态的影响。首先，将在mRNA、蛋白质以及功能水平上广泛比较来自健康对照和过敏性哮喘患者的幼稚外周血pDC。为了分析更分化的pDC，将使用建立的体外模型，其中在Th 2样细胞因子环境存在下将IL-3添加到幼稚pDC中以产生所谓的Th 2-pDC。为了分析该数据的体内相关性，将采用已建立的节段性变应原激发的人哮喘模型。在过敏原激发后，从支气管肺泡灌洗液中分离已在体内Th 2环境中分化的支气管内pDC，然后在Fcε RI交联后进一步分析。我们希望这些数据将使我们能够明确说明pDC在过敏性哮喘中是作为效应细胞还是作为免疫调节细胞发挥作用。最后，鉴于新的治疗策略的发展，我们想要鉴定其中和、抑制或添加将增加Th 2-pDC的致耐受性潜力并降低其Th 2效应物潜力的因子。对于该尝试，将进行Th 2-pDC的体外模型。