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，如哮喘，是一种越来越重要的由支气管炎症引起的疾病，其特征是支气管高反应性和间歇性气道阻塞，气道中存在潜在的Th2细胞偏向性炎症反应。目前的治疗方法是支气管扩张剂或抗炎药物，如皮质类固醇、白三烯调节剂和抗ige治疗等。然而，目前的治疗方法无法治愈，一些患者对强抗炎治疗反应不佳。此外，长期使用类固醇可能会导致许多意想不到的副作用。因此，迫切需要探索新的、更有效的干预策略。靶向Th2细胞及其产物的功能已被认为是开发潜在的过敏性哮喘独立治疗的有效策略。在早期疾病发展中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地输送到气道中，可以有效地直接干扰过敏原特异性Th2细胞的早期功能活化。然而，内衬气道的极化上皮单层形成粘膜屏障，不受大分子扩散的影响。这一屏障对免疫治疗蛋白的有效递送造成了很大的困难，使其无法进入气道中潜在的免疫效应细胞（如Th2细胞）并与之串扰。我们最近的研究表明，人CD23受体具有在人肺和支气管上皮细胞间转运IgE抗体的功能。在本研究中，我们进一步提出在小鼠过敏模型中研究CD2通过气道粘膜屏障传递靶向干扰CD4 Th2细胞功能的免疫治疗蛋白的可行性。因此，这些研究很可能导致大大改进的新疗法，以预防和潜在地治愈哮喘和过敏性疾病。