IN VIVO REGULATION OF IGE PRODUCTION

IGE 产生的体内调节

• 批准号: 6691099
• 负责人: Juan Lafaille
• 金额: $ 33万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6691099
• 关键词: B cell receptor; B lymphocyte; antibody formation; cell cell interaction; gene expression; gene rearrangement; genetically modified animals; helper T lymphocyte; immunoglobulin A; immunoglobulin E; immunoglobulin G; immunoglobulin genes; interferon gamma; interleukin 4; interleukin 5; laboratory mouse; microorganism hemagglutinin; receptor binding; respiratory hypersensitivity

DESCRIPTION: (Adapted from the Investigator's abstract): Exacerbated immune responses to environmental airborne non-pathogenic antigens (allergens) are one of the main factors for the development of asthma. Allergic reactions in the airways are triggered by antigen crosslinking of IgE molecules on mast cells, leading to degranulation and release of active mediators of smooth muscle constriction and inflammation. It has been shown that one of the essential determinant of allergic responses is the stimulation of T helper lymphocytes of the type 2 (Th2), which, through cognate T/B interaction and IL-4 secretion mediate B lymphocyte switch to IgE production, and through the secretion of IL-5, regulate the recruitment, differentiation and activation of eosinophils. This application is focused on the in vivo regulation of IgE production. Using homologous recombination, we have inserted a rearranged VDJ heavy chain gene as well as a rearranged VJ light chain gene from an influenza hemagglutinin-specific B cell hybridoma into the genome of mice. B cells from these mice maintain the physiological elements controlling somatic hypermutation and isotype switching, but, contrary to normal mice, the fate of antigen-specific cells can be easily followed. These mice will enable us to assess the relative importance of the different signals which promote isotype switching to IgE, thus defining ways in which the generation of IgE could be prevented or downregulated. Specifically, we will: 1) determine the conditions which favor the generation of antigen-specific IgE in vivo; 2) assess the importance of the affinity of the B cell receptor for its antigen on immunoglobulin class switch; 3) determine whether non-IgE antibodies expressing the same antigen-specificity of IgE antibodies can modulate the response in the airways, and 4) determine whether T cells are involved in the downregulation of IgE responses. We believe that the proposed experiments will enhance our knowledge on the regulation of IgE production in response to antigen, and will open new avenues for therapy of atopic disease.

描述：(改编自《调查者摘要》)：免疫加剧 对环境空气传播的非致病抗原(过敏原)的反应是一种 哮喘发生发展的主要因素。过敏性反应 呼吸道是由肥大细胞上IgE分子的抗原交联物触发的， 导致平滑肌活性介质的脱颗粒和释放 收缩和发炎。事实证明，最重要的因素之一 过敏反应的决定因素是T辅助淋巴细胞的刺激 2型(Th2)，通过同源T/B相互作用和IL-4分泌 介导B淋巴细胞向免疫球蛋白E的产生，并通过分泌 IL-5调节嗜酸性粒细胞的募集、分化和激活。 这方面的应用主要集中在体内对IgE产生的调节。vbl.使用 同源重组，我们插入了一个重排的VDJ重链基因 以及流感病毒的重排主播轻链基因 将血凝素特异性B细胞杂交瘤导入小鼠基因组。B细胞来源 这些小鼠维持着控制体细胞生长的生理因素 高突变和同型转换，但与正常小鼠相反， 抗原特异性细胞很容易被跟踪。这些老鼠将使我们能够 评估促进同种异型的不同信号的相对重要性 改用IgE，从而定义了产生IgE的方式 被阻止的或被削弱的。具体来说，我们会： 1)确定有利于产生抗原特异性IgE的条件 活体内； 2)评估B细胞受体对其抗原的亲和力的重要性 关于免疫球蛋白类开关； 3)确定非IgE抗体是否表达相同的抗原特异性 IgE抗体可以调节呼吸道的反应，并且 4)确定T细胞是否参与了IgE的下调 回应。 我们相信，拟议的实验将加强我们对 调节IgE的产生以响应抗原，并将开辟新的途径 用于治疗特应性疾病。