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、可能危及生命的恶化。鼻病毒（RV）占儿童哮喘发作的60-70%。尽管每当细胞病变炎症反应叠加在哮喘肺上时，就会预测哮喘加重，但这并不是观察到的-只有RV感染始终与哮喘加重有关。rv相关的恶化与2型细胞因子特征（IL-4， -5和-13）的增加有关，一种解释是这些细胞因子是由rv特异性T细胞本身产生的，无论是CD4+辅助（th2样）还是CD8+细胞毒性（tc2样）T淋巴细胞。对病毒感染作出反应的T淋巴细胞会产生对宿主有害的炎症反应。病情恶化还与抗炎细胞因子IL-10表达减少有关。IL-10可能控制与旺盛的T细胞反应相关的附带损伤。我们认为，在感染过程中，IL-10的来源很可能是效应T细胞本身。目的/假设：我们建议关注RV特异性效应/记忆t细胞产生的2型细胞因子和IL-10，预测自然RV感染后哮喘恶化的发展。我们假设，在RV感染期间病情恶化的儿童和青少年的RV特异性记忆T细胞释放较高水平的2型细胞因子和/或较低水平的IL-10。我们将鉴定感染RV的哮喘儿童，并验证我们鉴定循环RV特异性CD4+辅助淋巴细胞和CD8+细胞毒性T效应淋巴细胞的能力。具体目标#1将纳入哮喘儿童和青少年，我们将对他们进行RV感染的前瞻性评估，并量化对他们哮喘的影响。RV感染将在常规门诊就诊和上呼吸道感染提示时通过鼻腔分泌物的定量PCR诊断。RV感染的影响将主要通过对甲胆碱敏感性的改变来评估。我们的初步研究表明，在秋季RV大流行期间，50%的儿童将表现出感染的证据，其中约一半的感染将与哮喘加重有关，其定义为对甲胆碱敏感性增加2倍。特异性目标#2将研究rv特异性T细胞协调哮喘恶化的概念。我们将评估急性RV感染后循环中RV特异性T记忆细胞的患病率和细胞因子谱。我们将鉴定rv特异性记忆T细胞，并定义它们产生的1型（IFN-3）和2型细胞因子（IL-4、-5和-13）。我们将同时定义IL-10的细胞生成。我们提出，在hbv特异性辅助性（CD4+）和细胞毒性（CD8+）效应/记忆T细胞中，高2型/低IL-10细胞因子谱将预测哮喘恶化。