Defining the impact of dendritic cells on regulatory T cell induction and stability during asthma

慢性炎症是哮喘的基础，它可能调节致耐受性机制的诱导和抵抗。此外，修饰的树突状细胞（DC）和调节性T细胞（Treg）的激活和功能已在慢性炎症性疾病中报道，但尚未在哮喘中得到解决。在与葛兰素史克（GSK）正在进行的合作的基础上，该项目将使用患者样本和小鼠模型以及体内，体外和体外实验方法的组合来确定哮喘如何影响DC和TCLs之间的激活和对话。利用与曼彻斯特过敏，呼吸和胸外科生物库（ManARTS）的合作，我们将从哮喘供体中获得血液，痰液和肺切除组织，以使用多参数流式细胞术和高维数据分析对哮喘期间的DC，Treg和效应T细胞（Teff）亚群比例和激活状态进行高水平的了解。然后，这些数据将用于告知离体测定，以解决哮喘如何改变人DC和TcB的功能，并指导在过敏性气道炎症的精制小鼠模型中的机制研究。我们的目标是发现新的免疫网络和机制，这些网络和机制可以用于未来开发创新的、定制的人类哮喘疗法。更广泛地说，这个与GSK的合作项目将为疾病机制提供新的见解，以更好地定制现有的治疗方法，并支持新疗法的开发，用于肺部，肠道和其他组织的炎症性疾病。

Chronic inflammation that underlies asthma likely modulates both induction of, and resistance to, tolerogenic mechanisms. Further, modified dendritic cell (DC) and regulatory T cell (Treg) activation and function has been reported in chronic inflammatory disease settings, but has not yet been addressed in asthma. Building on ongoing collaboration with GlaxoSmithKline (GSK), this project will define how asthma influences activation of, and dialogue between, DCs and Tregs, using patient samples and murine models and a combination of in vivo, ex vivo and in vitro experimental approaches. Taking advantage of collaboration with the Manchester Allergy, Respiratory and Thoracic Surgery biobank (ManARTS), we will obtain blood, sputum and lung resection tissue from asthmatic donors to generate a high-level understanding of DC, Treg and effector T cell (Teff) subset proportions and activation states during asthma, using multi-parameter flow cytometry and high-dimensional data analysis. This data will then be used to inform ex vivo assays addressing how asthma modifies the function of human DCs and Tregs, and direct mechanistic studies in refined murine models of allergic airway inflammation. Our goal is to discover novel immune networks and mechanisms that can be targeted for future development of innovative, tailored, human asthma therapies. More broadly, this collaborative project with GSK will provide novel insight into disease mechanisms to better tailor existing treatments, and support the development of new therapeutics, for inflammatory diseases of the lung, intestine and other tissues.