Epithelial cell-antigen presenting cell crosstalk in the maintenance of immune homeostasis in the lung

ICASE博士的目的是应用一种新颖的、开创性的体外肺灌注（EVLP）模型来评估健康和病变组织环境下的免疫反应。这项研究是与葛兰素史克（GSK）合作进行的，并纳入了一个工业培训项目。在气体交换过程中，肺部暴露在各种各样的病原体、过敏原和无害颗粒中。专业抗原呈递细胞（APC）驻留在气道中，通过吸入颗粒对气道腔进行采样，作为免疫监测过程的一部分。APC能够在其局部环境中检测到各种刺激，这是由于它们表达了多种病原体识别受体（PRR），这使得能够检测外来颗粒，经历成熟和直接适应性t辅助细胞介导的免疫反应。这种识别过程导致免疫细胞的发育、激活和/或募集，这些免疫细胞需要根除入侵的实体。相反，为了限制对惰性颗粒的异常炎症反应，APC也可以由气道上皮细胞（AEC）指示适应耐受性表型并维持体内平衡。因此，AEC和APC之间的适当串扰对于维持肺稳态和产生针对病原体的生产性适应性免疫应答至关重要。考虑到这种平衡，AEC和apc之间的串扰失调也会导致肺部炎症，例如哮喘。进一步了解AEC和APCs在体内和体外复杂系统中的相互作用，可以帮助我们确定新的调控途径和新的免疫治疗靶点。为了研究AEC-APC串扰的作用，我们将使用一种新颖的体外肺灌注（EVLP）模型。利用这些独特的系统，我们可以在组织的生理环境中研究肺免疫的表型，并表征AEC和APC串扰在正常肺功能或对颗粒或病原体的反应中的作用。EVLP模型的使用意义重大，因为它提供了一个“在人体中首次使用前”的系统来评估药物递送的影响，并具有在健康和病变组织环境中使用的潜力。这项研究将跨越曼彻斯特炎症研究合作中心和葛兰素史克。将为Rebecca提供EVLP系统的广泛培训，体外分析包括原代细胞培养，免疫分析，基因表达分析，以及通过最先进的18参数流式细胞术进行细胞表型分析。

The aim of this ICASE PhD is to apply a novel and pioneering ex vivo lung perfusion (EVLP) model to assess the immune response in healthy and diseased tissue settings. The research is in partnership with GSK and incorporates an industrial training placement.During gaseous exchange the lungs are exposed to a vast variety of pathogens, allergens and innocuous particles. Professional antigen presenting cells (APC) reside in the airways, sampling the airway lumen by taking up inhaled particles as part of immune monitoring processes. APC are able to detect a variety of stimuli in their local environment due to their expression of a diverse array of pathogen recognition receptors (PRR), which enables the detection of foreign particles, undergo maturation and direct adaptive T-helper cell mediated immune responses. This recognition process results in the development, activation, and/or recruitment of immune cells required to eradicate the invading entity. Conversely, in order to limit aberrant inflammatory responses to inert particles, APC can also be instructed by airway epithelial cells (AEC) to adapt a tolerogenic phenotype and maintain homeostasis. Therefore, appropriate cross-talk between AEC and APC is critical to maintain lung homeostasis and generate productive adaptive immune responses against pathogens. With this balance in mind, the dysregulation of cross-talk between AEC and APCs is also known to contribute to inflammatory conditions in the lungs, e.g. asthma. Understanding further the interactions between AEC and APCs in complex in vivo, as well as in vitro systems, could lead us to identify new regulatory pathways and novel targets for immunotherapy.To study the role of AEC-APC crosstalk, we will use a novel and pioneering ex vivo lung perfusion (EVLP) model. Using these unique systems we can study the phenotype of lung immunity in a physiologic environment in the tissue and characterize the role of AEC and APC cross-talk during normal lung function or in response to particles or pathogens.The use of the EVLP model is significant, as it provides a "pre-first time in human" system to assess the impact of drug delivery with the potential for use in both healthy and diseased tissue settings. This study will span the Manchester Collaborative Centre for Inflammation Research and GSK. Extensive training will be provided to Rebecca in the EVLP system, in vitro assays including primary cell culture, immunoassays, gene expression analyses, and cellular phenoptyping by state of the art 18-parameter flow cytometry.