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

这个ICASE博士的目的是应用一种新的和开创性的离体肺灌注（EVLP）模型来评估健康和患病组织环境中的免疫反应。这项研究是与GSK合作进行的，并结合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。专职抗原呈递细胞（APC）驻留在气道中，作为免疫监测过程的一部分，通过摄取吸入的颗粒对气道腔进行采样。APC能够检测其局部环境中的各种刺激，这是由于它们表达多种病原体识别受体（PRR），这使得能够检测外来颗粒，经历成熟并直接适应性T辅助细胞介导的免疫应答。这种识别过程导致根除入侵实体所需的免疫细胞的发育、激活和/或募集。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）指导以适应致耐受性表型并维持稳态。因此，AEC和APC之间的适当串扰对于维持肺部稳态并产生针对病原体的有效适应性免疫反应至关重要。考虑到这种平衡，也已知AEC和APC之间的串扰的失调有助于肺中的炎性病症，例如哮喘。进一步了解AEC和APC之间的相互作用，在复杂的体内，以及在体外系统中，可能会导致我们确定新的调节途径和免疫治疗的新靶点。为了研究AEC-APC串扰的作用，我们将使用一个新的和开拓性的离体肺灌注（EVLP）模型。使用这些独特的系统，我们可以研究组织中生理环境中肺免疫的表型，并表征在正常肺功能期间或响应于颗粒或病原体时AEC和APC串扰的作用。因为它提供了“人类的第一次”该系统用于评估药物递送的影响，具有在健康和患病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GSK。将为Rebecca提供EVLP系统、体外试验（包括原代细胞培养）、免疫测定、基因表达分析和通过最先进的18参数流式细胞术进行的细胞表型分析方面的广泛培训。

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.