The Role of IL4R Alpha in Neonatal RSV Immunopathology

IL4R Alpha 在新生儿 RSV 免疫病理学中的作用

基本信息

批准号：
8701225
负责人：
Stephania A Cormier
金额：
$ 37.5万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701225
关键词：
Abbreviations Ablation Adoptive Transfer Adult Age Age-Years Allergic Animals Antisense Oligonucleotides Apoptosis Asthma Bronchiolitis Cell surface Cells Cessation of life Childhood Childhood Asthma Complex Data Dendritic Cells Development Disease Down-Regulation Elderly Eosinophilia Epidemiologic Studies Epidemiology Exposure to Extrinsic asthma Functional disorder Genetic Polymorphism Goals Health Care Costs Human IL4R gene Immune Immune response Immunity Infant Infection Inflammation Interferon Receptor Interferons Interleukin-12 Interleukin-13 Interleukin-4 Knowledge Life Ligands Link Lung Lung diseases Mediating Modeling Morbidity - disease rate Mucous body substance Mus Myelogenous Neonatal Ovalbumin Pathogenesis Phenotype Population Predisposition Production Pulmonary Pathology Regulation Respiratory Syncytial Virus Infections Respiratory physiology Respiratory syncytial virus Risk Risk Factors Role Signal Pathway Signal Transduction Terminology Testing Th1 Cells Therapeutic Intervention Time Up-Regulation Vaccines age related airway hyperresponsiveness airway inflammation burden of illness cytokine immunopathology immunoregulation infancy innovation methacholine mortality mouse model neonate novel prevent programs response

项目摘要

DESCRIPTION (provided by applicant: Respiratory Syncytial Virus (RSV) is the leading cause of bronchiolitis in infants worldwide with healthcare costs estimated at $365-$585 million per year. Human epidemiological studies have identified age at initial infection as an independent risk factor for the development of childhood asthma. We have previously demonstrated in a mouse model that age of initial infection with RSV influences respiratory function in later life - infection of neonatal mice, d 7d of age, primes for a Th2 immune response that contributes to the development of long-term airways dysfunction. The mechanism(s) underlying the influence of age on the immune and pulmonary responses elicited in response to RSV infection remains obscure. Our preliminary data reveal that expression of IL-4Ra is developmentally regulated such that its expression declines on lung mDCs and Th1 cells as animals age (i.e. expression is highest in the neonate). Furthermore, downregulation of IL-4Ra expression during RSV infection in the neonate 1) inhibits the initial Th2 biased immune response and 2) protects against persistent Th2 immune deviation and pulmonary pathophysiology observed with secondary RSV infection in the adult. Our data support the expression of IL-4Ra in early life as a critical and novel age-dependent mechanism of severe RSV infection. Therefore, our hypothesis is that developmentally regulated expression of IL-4Ra on neonatal myeloid dendritic cells (mDCs) is responsible for biasing immune and pulmonary responses towards asthmatic type responses in later life. Specifically, our preliminary data suggest a unique mechanism whereby elevated levels of IL-4Ra on neonatal mDCs initiates a Th2-polarized immune response to RSV and signaling through IL-4Ra on neonatal Th1 cells results in their ablation. We will explore the validity of this hypothesis in the following specific aims: Aim 1 will determine if age-related expression of IL-4Ra on mDCs is responsible for altered mDC function in neonatal RSV infection resulting in an asthma-promoting DC. We will leverage conditional cell ablation and adoptive transfer strategies to determine the functional role of IL-4Ra on neonatal mDCs. Aim 2 will explore our prediction that elevated levels of IL-4Ra on neonatal Th1 cells are responsible for their specific ablation during neonatal RSV infection and for the persistence of the asthma phenotype following neonatal RSV infection. Aim 3 will demonstrate that exacerbation of allergic asthma in adult mice is due to an altered Th2- inducing mDC formed during neonatal RSV infection. The concepts presented here are novel; and the data derived from these studies are expected to have a positive paradigm-shifting impact in understanding RSV- mediated asthma.

描述（由申请人提供：呼吸道合胞病毒（RSV）是全球婴儿细支气管炎的主要原因，其医疗保健费用估计为每年365至5.85亿美元，每年为5.85亿美元。人类流行病学研究已确定初始感染时的年龄在以前的儿童哮喘发展中是一种独立的危险因素 - 我们以前曾在儿童哮喘中发挥作用。新生儿小鼠的年龄为7D，有助于长期气道功能障碍的Th2免疫反应的素数。（即新生儿中的表达最高）。我们的数据支持早期IL-4RA的表达是严重的RSV感染的关键和新颖的年龄依赖性机制。因此，我们的假设是，在新生儿髓样树突状细胞（MDC）上，IL-4RA的发育调节表达是导致对以后生命中对哮喘类型反应的免疫和肺反应的偏见。具体而言，我们的初步数据提出了一种独特的机制，即新生儿MDC上的IL-4RA水平升高启动对RSV的Th2极性免疫反应，并通过Neonatal Th1细胞对IL-4RA发出信号传导导致其消融。我们将在以下特定目的中探讨该假设的有效性：AIM 1将确定IL-4RA在MDC上与年龄相关的表达是否导致新生儿RSV感染中MDC功能的改变，从而导致哮喘促进的DC。我们将利用条件细胞消融和收养转移策略来确定IL-4RA在新生儿MDC上的功能作用。 AIM 2将探讨我们的预测，即新生儿TH1细胞对新生儿RSV感染期间的特定消融水平的升高以及新生儿RSV感染后哮喘表型的持续性。 AIM 3将表明，成年小鼠过敏性哮喘的加剧是由于在新生儿RSV感染过程中形成的Th2诱导MDC所致。这里提出的概念是新颖的。预计从这些研究中得出的数据将对理解RSV介导的哮喘产生阳性范式转移影响。