CD23-mediated immunotherapy on airway inflammation

CD23介导的气道炎症免疫治疗

基本信息

批准号：
8499250
负责人：
XIAOPING ZHU
金额：
$ 17.86万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
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：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8499250
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

项目摘要

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.

描述（由申请人提供）：过敏性气道炎症，例如哮喘，是由支气管炎症引起的日益重要的疾病，其特征是支气管性超反应性和间歇性气道阻塞，其基本的TH2细胞偏置炎症反应在气道中。该疾病目前已接受支气管扩张剂或抗炎性药物（例如皮质类固醇，白三烯修饰剂和抗IGE疗法等）的治疗。但是，目前的治疗方法尚未治愈，有些患者对强烈的抗炎疗法反应不佳。另外，使用长期类固醇可能会导致许多不希望的副作用。因此，非常需要和探索新颖，更有效的中间策略。已提出针对Th2细胞及其产物功能的靶向，以作为开发过敏性哮喘潜在独立治疗的有效策略。预期在早期疾病发育中，过敏原特异性TH2细胞的减少或消除会减少反复过敏性炎症的后果。因此，有效地将免疫治疗蛋白递送到气道道中可以有效并直接干扰过敏原特异性Th2细胞在其最早的相位功能中的活化。然而，气道衬里的偏振上皮单层形成粘膜屏障，这不受大分子扩散。该障碍在气道中有效地递送免疫治疗蛋白在与潜在的免疫效应细胞（例如Th2细胞）中访问和交叉对话构成了主要的困难。我们最近的研究表明，人CD23受体在功能上能够在人肺和支气管上皮细胞上转运IgE抗体。在这项研究中，我们进一步建议检查CD2提供免疫治疗蛋白的可行性，这些蛋白旨在干扰小鼠过敏模型中气道粘膜屏障。因此，这些研究很可能会大大改善新的疗法，以防止并可能治愈哮喘和过敏性疾病。