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Effect of Atopy on Dendritic Cell Antiviral Responses

特应性对树突状细胞抗病毒反应的影响

基本信息

批准号：
8515329
负责人：
MICHELLE A GILL
金额：
$ 37.35万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2011-08-08 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8515329
关键词：
Acute Adrenal Cortex Hormones Aftercare Allergens Allergic Antiviral Agents Antiviral Response Asthma Breathing Cells Clinical Clinical Trials Controlled Clinical Trials Dendritic Cells Development Disease Epidemiology Event Exposure to Extrinsic asthma Fc Receptor Figs - dietary Frequencies Gene Expression Health IgE Immunity In Vitro Individual Influenza Interferon Type I Interferons Knowledge Link Mediating Mission National Institute of Allergy and Infectious Disease Participant Pathogenesis Pathway interactions Patients Placebo Control Placebos Play Prevention Process Production Public Health RNA Viruses Randomized Regulator Genes Research Rhinovirus Role Serum Signal Transduction Source TLR7 gene Testing Therapeutic Viral Virus Virus Diseases anti-IgE atopy burden of illness comparative efficacy crosslink cytokine design falls improved in vivo innovation insight omalizumab prevent receptor respiratory respiratory virus response

项目摘要

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how respiratory viral infections and atopy synergistically contribute to the development of acute exacerbations in individuals with allergic asthma. Plasmacytoid dendritic cells (pDCs) play a critical role in directing antiviral responses through the secretion of massive concentrations of Type I interferons (IFN). Impaired in vitro IFN responses to respiratory viruses have been demonstrated in pDCs isolated from individuals with allergic asthma. Moreover, in vitro pDC IFN responses to virus are inhibited by IgE-dependent mechanisms. As both IgE and expression of its receptor (Fc?RI) on pDCs are elevated in individuals with this disease, there is ample opportunity for IgE-mediated inhibition of pDC antiviral responses in patients with allergic asthma. The objective in this proposal is to investigate the effect of reducing IgE in vivo on pDC IFN responses in vitro using cells isolated from participants in an upcoming NIAID- sponsored randomized, placebo controlled clinical trial entitled Preventative Omalizumab or Step-up Therapy for Severe Fall Exacerbations (PROSE). The PROSE trial is designed to compare the efficacy of 3 treatments - omalizumab (an anti-IgE therapy), inhaled corticosteroid boost therapy, and placebo - in reducing fall exacerbations in patients with allergic asthma; it thus provides the optimal clinical setting to test the effect of reducing IgE on pDC IFN responses to viruses. The overlying hypothesis of this proposal is that reducing IgE concentrations in patients with allergic asthma will increase pDC IFN responses and reverse the inhibitory effects of allergen stimulation on pDC IFN responses. The rationale underlying this proposal is that since impaired pDC antiviral IFN responses in patients with allergic asthma are linked to IgE-mediated inhibitory pathways, there should be a role for decreasing IgE in enhancing pDC IFN responses. We will test our hypothesis by pursuing two specific aims: 1) Determine how omalizumab impacts pDC IFN responses. We will test this by comparing pDC IFN secretion and IFN-regulatory gene expression in participants before and after omalizumab therapy; and 2) Determine the impact of omalizumab on allergen and IgE cross-linking mediated inhibition of pDC IFN responses. We will test this by comparing the inhibitory effect of allergic stimulation on viral-induced pDC IFN secretion and IFN-regulatory gene expression in participants before and after treatment. The innovation of the approach resides in its focus on pDCs and their role in the apparent antagonism between IgE-mediated events and antiviral responses as well as the integration of these mechanistic studies into the upcoming clinical trial. The proposed research is significant because improved pDC IFN synthesis following omalizumab therapy could result in a decreased frequency of asthma exacerbations following respiratory viral infections. Ultimately, the new knowledge obtained will uncover mechanisms underlying the link between IgE-mediated pathways and viral-induced IFN signaling in pDCs and provide new insights into the prevention of viral-induced asthma exacerbations.

描述(由申请人提供)：在了解呼吸道病毒感染和特应性疾病如何协同促进过敏性哮喘患者急性加重的发展方面存在根本差距。浆细胞样树突状细胞(PDC)通过分泌大量的I型干扰素(IFN)在指导抗病毒反应中发挥重要作用。从过敏性哮喘患者中分离的pDC对呼吸道病毒的体外干扰素反应受损。此外，在体外，PDC对病毒的干扰素反应被IgE依赖的机制抑制。由于IgE及其受体(Fc？RI)在过敏性哮喘患者的pDC上的表达均升高，因此，在过敏性哮喘患者中，IgE介导的pDC抗病毒反应有很大的机会被抑制。这项建议的目的是利用从NIAID赞助的即将进行的名为预防性奥马珠单抗或严重秋季加重的加强疗法(SPRSE)的随机安慰剂对照临床试验参与者中分离的细胞，研究体内降低IgE对PDC干扰素体外反应的影响。这项散文试验旨在比较3种治疗方法--奥马珠单抗(一种抗IgE疗法)、吸入皮质类固醇强化疗法和安慰剂-在减少过敏性哮喘患者秋季发作方面的疗效；因此，它提供了最佳的临床环境，以测试降低IgE对PDC干扰素对病毒的反应的影响。这一建议的基本假设是，降低过敏性哮喘患者的IgE浓度将增加PDC干扰素反应，并逆转变应原刺激对PDC干扰素反应的抑制作用。这一建议的基本原理是，由于过敏性哮喘患者PDC抗病毒干扰素反应受损与IgE介导的抑制途径有关，因此降低IgE在增强PDC干扰素反应中应该发挥作用。我们将通过追求两个具体目标来验证我们的假设：1)确定奥马珠单抗如何影响PDC干扰素反应。我们将通过比较受试者在奥马珠单抗治疗前后的PDC干扰素分泌和干扰素调节基因表达来测试这一点；以及2)确定奥马珠单抗对过敏原和IgE交联介导的PDC干扰素反应抑制的影响。我们将通过比较过敏刺激对病毒诱导的PDC干扰素分泌和受试者治疗前后干扰素调节基因表达的抑制作用来检验这一点。该方法的创新之处在于它专注于pDC，它们在IgE介导的事件和抗病毒反应之间的明显拮抗中所起的作用，以及将这些机制研究整合到即将到来的临床试验中。这项拟议的研究意义重大，因为奥马珠单抗治疗后PDC干扰素合成的改善可能会降低呼吸道病毒感染后哮喘恶化的频率。最终，获得的新知识将揭示pDC中IgE介导的通路和病毒诱导的干扰素信号之间潜在的联系机制，并为预防病毒诱导的哮喘恶化提供新的见解。