Defining the importance of IL-25 in rhinovirus-induced asthma exacerbations

哮喘是最常见的呼吸道疾病，近几十年来有所增加，在许多欧洲国家，约30%的儿童在去年报告了喘息。鼻病毒（RV）感染是成人和儿童急性加重的主要个体原因。尽管存在大量相关疾病，但目前的治疗方法无效，并且对RV诱导的哮喘急性发作的机制知之甚少。哮喘患者在肺中产生一种分子IL-25，它在导致病情加重方面可能很重要。我们的目标是了解IL-25在RV感染和哮喘急性发作的免疫反应中的作用，并确定这种分子是否是开发更好治疗方法的合适候选者。为了确定IL-25是否与调节急性发作严重程度的免疫应答相关，我们开发了人类实验RV诱导的哮喘急性发作模型。本研究的临床样本将使我们能够研究IL-25表达与引起哮喘急性发作的宿主反应之间的关系。为了支持人类研究我们最近开发了世界？他的第一个鼻病毒感染和哮喘恶化的小鼠模型证明了许多与哮喘相关的结果，这些结果在小鼠中因感染而加剧。这些鼻病毒感染和哮喘恶化的小鼠模型将使得能够在哺乳动物气道内进行研究，以确定IL-25在疾病中的因果作用。因此，本提案的目的是利用鼻病毒诱导的哮喘急性发作的人类模型来确定IL-25在免疫应答和气道疾病中的作用，这是开发哮喘急性发作更好治疗方法的基础研究。

Asthma is the most common respiratory disease and has increased over recent decades, such that in many European countries ~30% of children now report wheeze in the last year. Rhinovirus (RV) infection is the dominant individual cause of acute exacerbations in both adults and children. Despite the enormous associated illness current therapies are ineffective and the mechanisms of RV induced asthma exacerbations are poorly understood. Asthmatics produce a molecule in their lungs, IL-25, that is potentially important in causing exacerbations. We aim to understand the role of IL-25 in immune responses to RV infections and asthma exacerbations and determine if this molecule is a suitable candidate for development of better treatments. To determine if IL-25 is associated with immune responses that regulate exacerbation severity we have developed a human experimental RV-induced asthma exacerbation model. Clinical samples from this study will enable us to investigate the association between IL-25 expression and host responses that cause asthma exacerbations. To support human studies we have recently developed the world?s first mouse models of rhinovirus infection and exacerbation of asthma demonstrating numerous asthma related outcomes exacerbated by infection in the mouse. These mouse models of rhinovirus infection and asthma exacerbation will enable investigation within the mammalian airway to establish a causal role in disease for IL-25. The objective of this proposal is therefore to utilize human and models of rhinovirus-induced asthma exacerbation to define a role for IL-25 in the immune response and airways disease, research fundamental to the development of better treatments for asthma exacerbations.