IN VIVO REGULATION OF IGE PRODUCTION

IGE 产生的体内调节

• 批准号: 6132491
• 负责人: Juan Lafaille
• 金额: $ 28.26万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6132491
• 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; interleukin 4; interleukin 5; laboratory mouse; microorganism hemagglutinin; receptor binding

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 cognitive allergic responses is the stimulation of T helper lymphocytes of the type 2(Th2), which, through cognitive 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 gene from an influenza hemagglutinin-specific B 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 cells, 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 down-regulated. 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 down-regulation 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.

对环境空气传播的非致病性抗原（过敏原）的免疫反应加剧是哮喘发展的主要因素之一。气道中的过敏反应是由肥大细胞上的IgE分子的抗原交联引发的，导致脱颗粒并释放平滑肌收缩和炎症的活性介质。已经表明，过敏反应的基本决定因素之一是刺激2型T辅助淋巴细胞（Th 2），其通过认知过敏反应刺激2型T辅助淋巴细胞（Th 2），其通过认知T/B相互作用和IL-4分泌介导B淋巴细胞转换为IgE产生，并通过IL-5分泌调节募集，嗜酸性粒细胞的分化和活化。本申请集中于IgE产生的体内调节。使用同源重组，我们已经插入了一个重排的VDJ重链基因，以及重排的VJ轻基因从流感血凝素特异性B杂交瘤到小鼠的基因组。来自这些小鼠的B细胞保持控制体细胞超突变和同种型转换的生理要素，但是，与正常细胞相反，抗原特异性细胞的命运可以容易地跟随。这些小鼠将使我们能够评估促进同种型转换为IgE的不同信号的相对重要性，从而确定可以预防或下调IgE产生的方法。具体而言，我们将：1）确定有利于体内产生抗原特异性IgE的条件; 2）评估B细胞受体对其抗原的亲和力对免疫球蛋白类别转换的重要性; 3）确定表达与IgE抗体相同的抗原特异性的非IgE抗体是否可以调节气道中的应答，和4）确定T细胞是否参与IgE应答的下调。我们相信，拟议的实验将提高我们的知识，调节IgE的生产响应抗原，并将开辟新的途径，特应性疾病的治疗。