IN VIVO REGULATION OF IGE PRODUCTION

描述：（改编自研究者的摘要）：免疫加剧 对环境空气传播的非致病性抗原（过敏原）的反应是其中之一 哮喘发生的主要因素。过敏反应在 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脱颗粒和释放 收缩和炎症。事实证明，重要的因素之一是 过敏反应的决定因素是辅助T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 淋巴细胞转而产生 IgE，并通过分泌 IL-5，调节嗜酸性粒细胞的募集、分化和激活。 该应用的重点是 IgE 产生的体内调节。使用 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 血凝素特异性 B 细胞杂交瘤进入小鼠基因组。 B 细胞来自 这些小鼠维持控制躯体的生理元素 超突变和同种型转换，但是，与正常小鼠相反， 可以轻松追踪抗原特异性细胞。这些老鼠将使我们能够 评估促进同种型的不同信号的相对重要性 转向 IgE，从而定义了 IgE 生成的方式 预防或下调。具体来说，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细胞受体与其抗原的亲和力的重要性 免疫球蛋白类别转换； 3) 确定非IgE抗体是否表达相同的抗原特异性 IgE 抗体可以调节气道的反应，并且 4）确定T细胞是否参与IgE的下调 回应。 我们相信所提出的实验将增强我们对 调节 IgE 产生以响应抗原，并将开辟新途径 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.