IGE MEDIATED BRONCHIAL RESPONSES TO ALLERGEN

IGE 介导支气管对过敏原的反应

• 批准号: 2758877
• 负责人: Hans C Oettgen
• 金额: $ 14.82万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2758877
• 关键词: B lymphocyte; allergens; antigen presentation; asthma; bronchomotion; disease /disorder model; enzyme linked immunosorbent assay; immunoglobulin E; inflammation; laboratory mouse; laboratory rat; leukocyte activation /transformation; polymerase chain reaction; radioimmunoassay; respiratory airflow measurement; respiratory epithelium; respiratory hypersensitivity; tissue /cell culture

Patients with asthma have an eosinophilic inflammation of the bronchial mucosa and display two distinct physiologic responses of the airways: bronchial hyperreactivity to nonspecific stimuli (BHR) and acute allergen-induced airflow obstruction following inhalation of specific allergens. There are strong clinical and epidemiological correlations between asthma and IgE production. Multiple established functions of IgE may contribute to asthmatic pathophysiology and blockers of IgE and its receptors are currently being studied as potential therapeutic agents. A number of murine models of asthma, including those established in this laboratory, have been utilized to examine the pathogenesis of two of the important aspects of the asthmatic response: allergen-induced eosinophilic inflammation of the airway mucosa and BHR. Using IgE-deficient mice (IgE-/-) previously generated by gene-targeting, we have shown that both eosinophilic airways inflammation and BHR (increased sensitivity to non-specific stimuli) can arise by IgE-independent pathways. To date, however, the existing models have not permitted analysis of other crucial features of the disease, acute airflow obstruction provoked by allergen inhalation and IgE-mediated amplification of local cellular and humoral immune responses in the bronchial mucosa. Novel approaches for the study of these responses have now been established by the P.I. and will be used to examine several hypotheses regarding the role of IgE. We hypothesize that allergen-specific IgE is a critical trigger of acute airflow obstruction following allergen inhalation and will address this question by bronchoprovocation studies in allergen-sensitized wild-type and IgE-/- mice. We have shown that IgE enhances CD23 expression and propose that this upregulation enhances the ability of B cells bearing IgE via CD23 to present antigen to allergen specific T cells. This hypothesis will be studied by testing the ability of B cells from wild-type, IgE-/-and CD23-/- mice to present antigen to antigen-specific T cells. Furthermore, we propose that IgE facilitates antigen focusing in the inflamed bronchial mucosa, leading to enhanced cellular and humoral responses in settings of recurrent allergen exposure and providing a mechanism for the phenomenon of allergic spread. We will compare the immune responses of wild-type and IgE-/- mice following bronchial allergen exposure performed in the presence and absence of actively-induced or passively administered specific IgE.

哮喘患者的支气管黏膜有嗜酸性炎症，并表现出两种截然不同的呼吸道生理反应：对非特异性刺激的高反应性(BHR)和吸入特定过敏原后急性过敏原诱导的气流阻塞。哮喘和IgE的产生有很强的临床和流行病学相关性。多种已建立的免疫球蛋白功能可能参与了哮喘的病理生理过程，目前正在研究免疫球蛋白及其受体的阻断剂作为潜在的治疗药物。许多小鼠哮喘模型，包括那些在本实验室建立的模型，已经被用来研究哮喘反应的两个重要方面的发病机制：过敏原诱导的气道粘膜嗜酸性炎症和BHR。使用以前通过基因打靶产生的IgE缺陷小鼠(IgE-/-)，我们已经证明嗜酸性气道炎和BHR(对非特异性刺激的敏感性增加)都可以由非IgE依赖的途径引起。然而，到目前为止，现有的模型还不能分析疾病的其他关键特征，过敏原吸入引起的急性气流阻塞，以及IgE介导的支气管粘膜局部细胞和体液免疫反应的放大。P.I.现在已经建立了研究这些反应的新方法，并将用于检验关于IgE作用的几个假说。我们假设过敏原特异性的IgE是吸入过敏原后急性气流阻塞的关键触发因素，并将通过对过敏原致敏的野生型和IgE-/-小鼠进行支气管激发研究来解决这个问题。我们已经证明，IgE增强了CD23的表达，并提出这种上调增强了通过CD23携带IgE的B细胞向变应原特异性T细胞递呈抗原的能力。这一假设将通过测试来自野生型、IgE-/-和CD23-/-小鼠的B细胞向抗原特异性T细胞呈递抗原的能力来研究。此外，我们认为，IgE促进了发炎的支气管粘膜中的抗原聚集，导致在反复接触变应原的情况下增强了细胞和体液反应，并为过敏传播现象提供了一种机制。我们将比较野生型和IgE-/-小鼠在存在和不存在主动诱导或被动注射特异性IgE的情况下暴露于支气管变应原后的免疫反应。