An Evaluation of Treatment with Omalizumab to Improve the Asthmatic Response to a

奥马珠单抗治疗改善哮喘反应的评估

基本信息

批准号：
8522153
负责人：
PETER W HEYMANN
金额：
$ 111.47万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-03 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8522153
关键词：
3 year old Accident and Emergency department Acute Admission activity Affect Aftercare Age-Years Allergens Allergic Allergic inflammation Antibodies Antigen-Presenting Cells Antigens Antiviral Response Asthma Basophils Biological Assay Blood Blood Circulation Breathing Bronchial Hyperreactivity CD14 gene CD4 Positive T Lymphocytes Capsid Caring Cells Child Childhood Clinical Clinical Trials Clinical Trials Design Coculture Techniques Common Cold Common Cold Virus Cost of Illness Dendritic Cells Development Disease Down-Regulation Effector Cell Employee Strikes Eosinophilia Epithelial Epitopes Evaluation Exhalation Extrinsic asthma FDA approved Flow Cytometry Frequencies Gases Harvest Health Care Costs Hospitalization Hospitals Hypersensitivity Hypersensitivity skin testing IgE IgE Receptors Immune In Vitro Individual Infection Inflammation Inflammatory Response Inhalant dose form Injection of therapeutic agent Institutional Review Boards Investigation Knowledge Lower respiratory tract structure Lung MHC Class II Genes Measurement Modeling Molecular Molecular Target Monitor Monoclonal Antibodies Morbidity - disease rate Myelogenous Natural Immunity Nitric Oxide Nose Outcome Pathway interactions Patients Peptide/MHC Complex Phase Phenotype Physicians Placebos Play Poaceae Population Preparation Process Property Published Comment Randomized Recording of previous events Research Design Respiratory System Respiratory physiology Respiratory tract structure Rhinovirus Risk Risk Factors Role Sampling Serologic tests Serum Staining method Stains Steroids Surface Symptoms T cell response T-Lymphocyte TSLP gene Testing Universities Viral Virginia Virus Virus Diseases Visit allergic response anti-IgE base cytokine design eosinophil falls human TSLP protein improved in vivo inflammatory marker insight memory CD4 T lymphocyte methacholine migration monocyte novel omalizumab prevent primary outcome pyroglyphid receptor response screening trafficking volunteer young adult

项目摘要

DESCRIPTION (provided by applicant): Exacerbations of asthma requiring unscheduled physician visits, emergency department care, or hospital admission are a major cause of the morbidity and cost of this disease, which affects up to 8% of the population. Extensive evidence suggests that a large proportion of these exacerbations during childhood (after three years of age) and among young adults are triggered by a viral infection, predominantly infections caused by rhinovirus (RV). In addition, a large body of evidence shows that patients who develop an exacerbation with RV are allergic to one or more common inhalant allergens. When patients presenting with acute asthma are studied in an emergency department, they have evidence of inflammation, which is usually interpreted as being part of the response to the virus. However, previous results using the RV challenge model suggest that inflammation, as judged by exhaled nitric oxide (FeNO) or eosinophilia, is as much a risk factor for a pulmonary response to the virus as it is a response that occurs during the viral infection. The mechanistic basis for this synergistic interaction between the viral infection and pre-existing allergy is not known. The clinical trial proposed here (AIM 1) is to treat subjects, who have allergic asthma, for two months with the monoclonal antibody omalizumab (anti-IgE) or placebo, prior to challenging them with the FDA-approved preparation of RV-39. This trial design has been approved by the FDA (FDA-BB-IND #10510) and the University of Virginia IRB. The primary outcome will be cumulative lower respiratory tract symptoms (CLTRS) during the first four days of infection. The patients will also be monitored for a wide range of markers relevant to inflammation of the respiratory tract, as well as for changes in cellular responses occurring during the viral infection. Thus, it will be possible to directly answer whether anti-IgE treatment is effective in reducing both lung symptoms and bronchial hyperreactivity because it decreases IgE and its receptor on relevant cells, or because it decreases inflammation prior to infection. The proposed cellular studies (AIM 2) will investigate whether anti-IgE treatment reduces the induction of allergen-specific or RV-specific CD4+ T cells with a Th2 cytokine signature. The capacity for anti-IgE to down-regulate Th2-promoting pathways in antigen presenting cells (DCs and possibly basophils) will be examined. In complementary T-cell studies, recent advances in the development of novel peptide/MHC II tetramers will be used to identify and enumerate circulating CD4+ T cells specific for allergen (grass and dust mite) and RV in parallel throughout the two-month treatment phase and subsequent RV challenge phase of the trial in order to monitor fluxes in these cells that correspond to migration to the inflamed respiratory tract. In conjunction, the capacity for RV infection to induce a Th2 profile and for anti-IgE treatment to ameliorate this effect will be assessed using in vitro cultures stimulated with allergen or RV. Taken together, these studies are designed to understand the importance of IgE antibodies and to better define the correct targets for the treatment of asthma that is designed to prevent exacerbations.

描述（由申请人提供）：哮喘需要外医生就诊，急诊科护理或住院入院的哮喘是这种疾病发病率和成本的主要原因，这影响了多达8％的人口。大量证据表明，在儿童期（三岁以后）和年轻人中，大部分这些加重是由病毒感染引发的，主要是由鼻病毒（RV）引起的。此外，大量证据表明，患有RV加重的患者对一种或多种常见的吸入过敏原过敏。当在急诊室研究急性哮喘的患者时，他们有炎症的证据，通常被解释为对病毒反应的一部分。但是，先前使用RV挑战模型的结果表明，按照呼出的一氧化氮（FENO）或嗜酸性粒细胞的判断，炎症是对病毒的肺部反应的危险因素，而这是病毒感染期间发生的一种反应。尚不清楚病毒感染与预先存在的过敏之间这种协同相互作用的机械基础。这里提出的临床试验（AIM 1）是治疗两个月的受试者，患有过敏性哮喘的受试者在通过FDA批准的RV-39制备挑战之前，使用单克隆抗体（抗IGE）或安慰剂。该试验设计已获得FDA（FDA-BB-IND＃10510）和弗吉尼亚大学IRB的批准。主要结果将是感染前四天的累积下呼吸道症状（CLTR）。患者会还可以监测与呼吸道炎症以及病毒感染期间细胞反应的变化有关的广泛标记。因此，将是可以直接回答抗IGE治疗是否有效减少肺症状和支气管高反应性，因为它会降低IgE及其受体在相关细胞上，或者因为它在感染前会降低炎症。拟议的细胞研究（AIM 2）将研究抗IGE处理是否会减少具有Th2细胞因子特异性或RV特异性CD4+ T细胞的诱导。将检查抗IgE下调抗原呈递细胞中Th2促进途径的能力（DCS和可能是嗜碱性粒细胞）。在互补的T细胞研究中，新型肽/MHC II四聚体的发展的最新进展将用于识别和枚举对过敏原（草和粉尘螨）特异性的循环CD4+ T细胞，并在整个两个月的治疗阶段和随后的RV攻击阶段平行地监测这些细胞中的Flux，并在整个两个月治疗阶段中平行地进行迁移，以使其对迁移的迁移进行迁移。结合起，将使用过敏原或RV刺激的体外培养物评估RV感染诱导Th2谱和抗IGE治疗的能力。综上所述，这些研究旨在了解IgE抗体的重要性，并更好地定义旨在防止加剧的哮喘治疗哮喘的正确靶标。