CD4+ and CD8+ T cell dependent immune mechanisms of rhinovirus-mediated asthma ex

鼻病毒介导的哮喘的 CD4 和 CD8 T 细胞依赖性免疫机制

• 批准号: 7975934
• 负责人: LARRY C BORISH
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7975934
• 关键词: Accounting; Acute; Adolescent; Allergic; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; CD4 Positive T Lymphocytes; CD8B1 gene; Caring; Cells; Cessation of life; Child; Childhood; Childhood Asthma; Clinic Visits; Common Cold; Data; Development; Diagnosis; Enrollment; Epitopes; Exhibits; Guidelines; Helper-Inducer T-Lymphocyte; Hospitalization; Immune; Immune system; Individual; Infection; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-4; Life; Link; Lung; Lung Inflammation; Lymphocyte; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Nose; Pathogenesis; Peripheral Blood Mononuclear Cell; Prevalence; Preventive Intervention; Production; Regulatory T-Lymphocyte; Respiratory Tract Infections; Rhinovirus; Risk; Role; Sampling; Severities; Source; Spirometry; Symptoms; T cell response; T memory cell; T-Lymphocyte; Testing; Upper Respiratory Infections; Viral; Virus; Virus Diseases; airway hyperresponsiveness; asthmatic patient; base; cytokine; cytotoxic; falls; methacholine; pandemic disease; public health relevance; response

DESCRIPTION (provided by applicant): The greatest morbidity associated with asthma is the occurrence of severe, potentially life- threatening exacerbations. Rhinovirus (RV) accounts for ~60-70% of childhood asthma exacerbations. Although an exacerbation would be predicted whenever a cytopathic inflammatory response is superimposed upon the asthmatic lung, this is not what is observed - and only RV infections are consistently associated with asthma exacerbations. RV-associated exacerbation are linked to the presence of an increased type 2 cytokine signature (IL-4, -5, and -13) and one explanation is that these cytokines are being produced by the RV-specific T cells themselves, either CD4+ helper (Th2-like) or CD8+ cytotoxic (Tc2-like) T lymphocytes. T lymphocytes responding to a viral infection produce inflammatory responses that can be harmful to the host. Exacerbations are also linked to the presence of diminished expression of the anti-inflammatory cytokine IL-10. IL-10 may to control the collateral damage associated with an exuberant T cell response. The source of this IL-10 during infection, we believe, is likely the effector T cells themselves. Objective/Hypothesis: We propose to focus on the production of type 2 cytokines and IL-10 by RV-specific effector/memory T-cells that predict the development of an asthma exacerbation following natural RV infection. We hypothesize that RV-specific memory T cells from children and adolescents who develop an exacerbation during RV infection release higher levels of type 2 cytokines and/or lower levels of IL-10. We will identify children with asthma who become infected with RV and validate our ability to identify circulating RV-specific CD4+ helper and CD8+ cytotoxic T effector lymphocytes. Specific aim #1 will enroll asthmatic children and adolescents who we will prospectively evaluate for RV infections and quantify the impact on their asthma. RV infection will be diagnosed by quantitative PCR of nasal secretions at regular clinic visits and when prompted by upper respiratory infections. Impact of RV infection will be evaluated primarily as change in methacholine sensitivity. Our preliminary studies demonstrate that during the fall RV pandemic >50% of children will demonstrate evidence for infection and ~half of those infections will be associated with an asthma exacerbation defined as a >2-fold increase in methacholine sensitivity. Specific aim #2 will examine the concept that RV-specific T cells orchestrate asthma exacerbations. We will assess the prevalence and cytokine profile of circulating RV-specific T memory cells after acute RV infections. We will identify RV-specific memory T cells and will define their production of type 1 (IFN-3) and type 2 cytokines (IL-4, -5, and -13). We will simultaneously define cellular production of IL-10. We propose that a high type 2/ low IL-10 cytokine profile within RV-specific helper (CD4+) and cytotoxic (CD8+) effector/memory T cells will predict asthma exacerbations. PUBLIC HEALTH RELEVANCE: The virus producing the "common cold" (rhinovirus) is responsible for most childhood and adolescent asthma exacerbations and, as such, most hospitalizations and deaths from asthma. The mechanism responsible for this unique feature of this virus is an enigma. Even though only a small subset of asthmatics is at risk for severe exacerbations, urgent care referral, hospitalization, or death, because of our inability to identify at risk individuals, current guidelines encourage aggressive daily treatment of all but the mildest asthmatics. Identifying the mechanism through which rhinovirus interacts with the immune system to produce an asthma exacerbation is central to identifying children who are at risk for asthma exacerbations and are most likely to benefit from specific interventions for prevention and treatment.

描述（由申请人提供）：与哮喘相关的最大发病率是发生严重的，潜在的威胁生命的加剧。鼻病毒（RV）约占儿童哮喘加重的60-70％。尽管每当细胞性炎症反应叠加在哮喘性肺上时，都会预测加剧，但这并不是观察到的 - 只有RV感染始终与哮喘发作持续相关。与RV相关的恶化与增加2型细胞因子特征（IL-4，-5和-13）的存在有关，并且一种解释是，这些细胞因子本身是由RV特异性T细胞本身产生的，即CD4+ Helper（Th2-like）或CD8+细胞毒性（TC8+细胞毒性（TC2-tc2like）tc2like）tlymphees t lymphees t lymphoce tlymphocey对病毒感染反应的T淋巴细胞会产生对宿主有害的炎症反应。恶化也与抗炎细胞因子IL-10的表达降低有关。 IL-10可能可以控制与繁殖T细胞反应相关的附带损害。我们认为，在感染期间，该IL-10的来源可能是效应T细胞本身。客观/假设：我们建议通过RV特异性效应子/记忆T细胞专注于2型细胞因子和IL-10的生产，以预测自然RV感染后哮喘加重的发展。我们假设来自儿童和青少年的RV特异性记忆T细胞在RV感染期间发展出加重的儿童和/或IL-10水平较低。我们将确定患有哮喘的儿童感染了RV，并验证我们鉴定循环RV特异性CD4+助手和CD8+细胞毒性T效应淋巴细胞的能力。特定目标＃1将招募哮喘儿童和青少年，我们将前瞻性评估RV感染并量化对其哮喘的影响。 RV感染将在常规诊所就诊时通过鼻分泌物的定量PCR诊断，并在受到上呼吸道感染的提示时诊断。 RV感染的影响将主要评估为甲基胆碱敏感性的变化。我们的初步研究表明，在秋季RV大流行期间，> 50％的儿童将证明感染的证据，其中一半的感染将与哮喘加重定义为甲基苯胺敏感性的增加> 2倍。特定的目标＃2将研究RV特异性T细胞协调哮喘加剧的概念。我们将评估急性RV感染后循环的RV特异性T记忆细胞的患病率和细胞因子谱。我们将识别RV特异性内存T细胞，并定义其1型（IFN-3）和2型细胞因子（IL-4，-5和-13）的产生。我们将同时定义IL-10的细胞产生。我们建议在RV特异性助手（CD4+）和细胞毒性（CD8+）效应子/记忆T细胞中，高型2/低IL-10细胞因子谱将预测哮喘的恶化。 公共卫生相关性：产生“普通感冒”（鼻病毒）的病毒是导致大多数童年和青少年哮喘加剧的原因，因此，大多数住院和哮喘死亡。负责该病毒独特特征的机制是一个谜。即使只有一小部分哮喘患者有严重加重，紧急护理转诊，住院或死亡的风险，因为我们无法识别危险的人，但当前的准则仍鼓励除最轻度哮喘以外的所有人对所有人进行积极的日常治疗。识别鼻病毒与免疫系统相互作用以产生哮喘加重的机制对于识别有哮喘患病风险的儿童至关重要，并且最有可能受益于预防和治疗的特定干预措施。