CD23-mediated immunotherapy on airway inflammation

CD23介导的气道炎症免疫治疗

• 批准号: 8358273
• 负责人: XIAOPING ZHU
• 金额: $ 22.8万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358273
• 关键词: Adrenal Cortex Hormones; Adult; Adverse effects; Affinity; Air; Allergens; Allergic; Allergic Disease; Allergic inflammation; Allergic rhinitis; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Presenting Cells; Apical; Asthma; Basophils; Binding; Biotin; Breathing; Bronchodilator Agents; Bronchus-Associated Lymphoid Tissue; CD28 gene; CD80 gene; CTLA4-Ig; Cell Line; Cell physiology; Cells; Chimeric Proteins; Chronic Obstructive Airway Disease; Cytotoxic T-Lymphocyte-Associated Protein 4; Dendritic Cells; Development; Diffusion; Disease; Effector Cell; Endocytic Vesicle; Endocytosis; Epithelial; Epithelial Cells; Epithelium; Exposure to; Extrinsic asthma; Fc Immunoglobulins; Fc Receptor; Functional disorder; Future; Histopathology; Human; Hypersensitivity; IgE; IgE Receptors; Immune; Immune response; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Infant; Inflammation; Inflammatory; Inflammatory Response; Knockout Mice; Label; Lead; Lectin; Leukotrienes; Liquid substance; Lung; Lymphocyte; Mediating; Membrane; Modeling; Mus; Ovalbumin; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Physiological; Proteins; Recombinants; Respiratory System; Respiratory tract structure; Route; Serum; Steroids; Surface; T-Cell Activation; Th2 Cells; Therapeutic Intervention; Tight Junctions; Time; Tissues; airway inflammation; airway obstruction; allergic airway inflammation; anti-IgE; apical membrane; base; basolateral membrane; effective therapy; eosinophil; human disease; improved; macromolecule; man; mast cell; monolayer; novel; protein transport; receptor; respiratory; response; therapeutic protein; transcytosis; uptake

DESCRIPTION (provided by applicant): Allergic airway inflammations, such as asthma, are an increasingly important disease caused by bronchial inflammation and characterized by bronchial hyper-responsiveness and intermittent airway obstruction with an underlying Th2 cell-biased inflammatory response in the airways. The disease is currently treated with bronchodilators or anti- inflammatory drugs such as corticosteroids, leukotriene modifiers, and anti-IgE therapy, etc. However, the current treatments are not curative and some patients do not respond well to intense anti-inflammatory therapies. Additionally, the use of long-term steroids may result in many undesired side effects. For this reason, novel and more effective intervening strategies are greatly needed and explored. Targeting of the functions of Th2 cells and their products have been proposed as an effective strategy for the development of potential stand-alone treatments for allergic asthma. The reduction or elimination of allergen-specific Th2 cells in early disease development is expected to reduce the consequences of repeated allergic inflammatory. Hence, efficient delivery of immunotherapeutic proteins into the airway tract could effectively and directly interfere with allergen-specific Th2 cell activation in its earliest phaseof function. However, the polarized epithelial monolayer lining the airway forms mucosal barrier which is impervious to macromolecule diffusion. This barrier poses a major difficulty for an efficient delivery of immunotherapeutic proteins to access and cross-talk with underlying immune effector cells, such as Th2 cells, in the airway. Our recent studies have shown that human CD23 receptor is functionally capable of transporting IgE antibody across human lung and bronchial epithelial cells. In this study, we further propose to examine the feasibility of CD2 to deliver the immunotherapeutic proteins, which are targeted to interfere with CD4 Th2 cell function, across airway mucosal barrier in a mouse allergy model. These studies, therefore, are very likely to lead to greatly improved novel therapies that protect against and potentially cure asthma and allergic diseases. PUBLIC HEALTH RELEVANCE: CD23-mediated immunotherapy on airway inflammation Airway inflammation, asthma, is among the most common diseases in both infant and adult. CD23 is capable of transporting IgE across airway epithelial cells. This study will explore the feasibility whether CD23 can deliver an immunotherapeutic protein to modulate or dampen the development of airway allergic inflammation.

描述（由申请人提供）：过敏性气道炎症，例如哮喘，是一种由支气管炎症引起的日益重要的疾病，其特征是支气管高反应性和间歇性气道阻塞，以及气道中潜在的Th2细胞偏向性炎症反应。目前该病的治疗主要采用支气管扩张剂或抗炎药物，如皮质类固醇、白三烯调节剂、抗IgE治疗等。但目前的治疗方法疗效不佳，部分患者对强效抗炎治疗反应不佳。此外，长期使用类固醇可能会导致许多不良副作用。因此，非常需要和探索新颖且更有效的干预策略。针对 Th2 细胞及其产物的功能已被提议作为开发潜在的过敏性哮喘独立治疗方法的有效策略。在疾病发展早期减少或消除过敏原特异性 Th2 细胞有望减少反复过敏性炎症的后果。因此，将免疫治疗蛋白有效递送到气道中可以有效地直接干扰过敏原特异性 Th2 细胞在其最早功能阶段的激活。然而，气道内衬的极化上皮单层形成粘膜屏障，该屏障不受大分子扩散的影响。这种屏障对于免疫治疗蛋白的有效递送以进入气道中的潜在免疫效应细胞（例如 Th2 细胞）并与其进行交叉对话造成了重大困难。我们最近的研究表明，人类 CD23 受体在功能上能够将 IgE 抗体转运穿过人类肺和支气管上皮细胞。在这项研究中，我们进一步建议在小鼠过敏模型中检查 CD2 传递免疫治疗蛋白的可行性，这些蛋白的目标是干扰 CD4 Th2 细胞功能，穿过气道粘膜屏障。因此，这些研究很可能会带来极大改进的新疗法，以预防和潜在治愈哮喘和过敏性疾病。 公共卫生相关性：CD23 介导的气道炎症免疫疗法 气道炎症、哮喘是婴儿和成人最常见的疾病之一。 CD23 能够转运 IgE 穿过气道上皮细胞。本研究将探讨 CD23 是否可以传递免疫治疗蛋白来调节或抑制气道过敏性炎症的发展。