IN VIVO REGULATION OF IGE PRODUCTION

描述：（改编自研究者摘要）：免疫加重 对环境空气传播的非致病性抗原（过敏原）的反应是一种 哮喘发病的主要因素。过敏反应 气道由肥大细胞上IgE分子的抗原交联触发， 导致平滑肌活性介质的脱粒和释放 收缩和炎症。事实证明，其中一个重要的 过敏反应的决定因素是刺激T辅助淋巴细胞， 2型（Th 2），其通过同源T/B相互作用和IL-4分泌 介导B淋巴细胞转换为IgE产生，并通过分泌 IL-5调节嗜酸性粒细胞的募集、分化和活化。 本申请集中于IgE产生的体内调节。使用 通过同源重组，我们插入了重排的VDJ重链基因， 以及来自流感病毒的重排VJ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细胞来自 这些小鼠保持控制躯体的生理因素， 超突变和同种型转换，但是，与正常小鼠相反， 可以容易地跟踪抗原特异性细胞。这些老鼠能让我们 评估促进同种型的不同信号的相对重要性 切换到IgE，从而定义了IgE产生的方式， 预防或下调。具体而言，我们将： 1)确定有利于抗原特异性IgE产生的条件 体内; 2)评估B细胞受体对其抗原的亲和力的重要性 免疫球蛋白类别转换; 3)确定表达相同抗原特异性的非IgE抗体 IgE抗体可以调节气道的反应， 4)确定T细胞是否参与IgE的下调 应答 我们相信，拟议的实验将增进我们对 调节免疫球蛋白E的生产，以响应抗原，并将开辟新的途径 用于治疗特应性疾病。

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.