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

这项iCASE PHD的目的是应用一种新的和开创性的体外肺灌注(EVLP)模型来评估健康和疾病组织环境中的免疫反应。这项研究与葛兰素史克合作，并纳入了一个工业培训场所。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。专业的抗原提呈细胞(APC)驻留在呼吸道中，通过摄取吸入的颗粒来采样呼吸道管腔，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，这是因为他们表达了一系列不同的病原体识别受体(PRR)，这使得他们能够检测到外来颗粒，经历成熟和直接适应性T辅助细胞介导的免疫反应。这一识别过程导致了根除入侵实体所需的免疫细胞的发展、激活和/或招募。相反，为了限制对惰性颗粒的异常炎症反应，气道上皮细胞(AEC)也可以指示APC适应耐受性表型并维持内稳态。因此，AEC和APC之间适当的串扰对于维持肺内稳态和产生针对病原体的高效适应性免疫反应至关重要。考虑到这一平衡，AEC和APC之间的串扰调节失调也被认为是导致肺部炎症的原因，例如哮喘。进一步了解AEC和APC在体内和体外复杂系统中的相互作用，可以引导我们发现新的调控途径和免疫治疗的新靶点。为了研究AEC-APC串扰的作用，我们将使用一个新颖的、开创性的体外肺灌流(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AEC和APC在正常肺功能期间或在对颗粒或病原体的反应中所起的作用。EVLP模型的使用具有重要意义，因为它提供了一个“人类第一次”系统来评估药物释放的影响，并有可能在健康和疾病组织环境中使用。这项研究将涉及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，包括体外细胞培养、免疫分析、基因表达分析和最先进的18参数流式细胞仪的细胞表型分析。

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.