Effect of Atopy on Dendritic Cell Antiviral Responses

描述（由申请人提供）：在理解呼吸道病毒感染和特应性如何协同促进过敏性哮喘个体急性加重的发展方面存在根本差距。浆细胞样树突状细胞（pDCs）通过分泌大量I型干扰素（IFN）在指导抗病毒反应中发挥关键作用。从过敏性哮喘个体分离的pDCs中已经证实体外IFN对呼吸道病毒的反应受损。此外，体外pDC - IFN对病毒的反应受到ige依赖机制的抑制。IgE及其受体(Fc？在哮喘患者中，ige介导的抑制pDC抗病毒反应的可能性很大。本提案的目的是研究体内降低IgE对pDC IFN体外反应的影响，使用从即将进行的NIAID赞助的随机、安慰剂对照临床试验参与者中分离的细胞，该试验名为预防性Omalizumab或加重治疗严重跌倒恶化（PROSE）。PROSE试验旨在比较3种治疗方法——奥玛珠单抗（一种抗ige治疗）、吸入皮质类固醇增强治疗和安慰剂——在减少过敏性哮喘患者跌倒加重方面的疗效；因此，它为测试降低IgE对pDC IFN对病毒反应的影响提供了最佳的临床环境。该建议的基础假设是，降低过敏性哮喘患者的IgE浓度会增加pDC IFN反应，并逆转过敏原刺激对pDC IFN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的pDC抗病毒IFN反应受损与IgE介导的抑制途径有关，因此降低IgE应该在增强pDC IFN反应中发挥作用。我们将通过追求两个特定目标来验证我们的假设：1)确定omalizumab如何影响pDC IFN反应。我们将通过比较参与者在奥玛单抗治疗前后的pDC IFN分泌和IFN调节基因表达来验证这一点；2)确定omalizumab对过敏原和IgE交联介导的pDC IFN反应抑制的影响。我们将通过比较过敏刺激对治疗前后参与者病毒诱导的pDC IFN分泌和IFN调节基因表达的抑制作用来验证这一点。该方法的创新之处在于其重点关注pDCs及其在ige介导的事件和抗病毒反应之间的明显拮抗作用，以及将这些机制研究整合到即将进行的临床试验中。这项研究具有重要意义，因为omalizumab治疗后pDC IFN合成的改善可能导致呼吸道病毒感染后哮喘发作频率的降低。最终，获得的新知识将揭示ige介导的途径和病毒诱导的pDCs中IFN信号传导之间联系的机制，并为预防病毒诱导的哮喘恶化提供新的见解。

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.