IN VIVO REGULATION OF IGE PRODUCTION

对环境空气传播的非致病抗原(过敏原)的免疫反应加剧是哮喘发生的主要因素之一。呼吸道中的过敏反应是由肥大细胞上的IgE分子的抗原交联性引发的，导致脱颗粒和释放活性的平滑肌收缩和炎症介质。研究表明，过敏反应的基本决定因素之一是刺激2型辅助性T淋巴细胞(Th2)，Th2通过认知性变态反应刺激2型辅助性T淋巴细胞(Th2)，Th2通过认知T/B相互作用和IL-4分泌介导B淋巴细胞向IgE的产生，并通过IL-5的分泌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。通过同源重组，我们从流感血凝素特异性B杂交瘤中插入了重排的VDJ重链基因和重排的VJ轻基因到小鼠的基因组中。来自这些小鼠的B细胞维持着控制体细胞超突变和同型转换的生理要素，但与正常细胞相反，抗原特异性细胞的命运很容易被跟踪。这些小鼠将使我们能够评估促进同型转换为IgE的不同信号的相对重要性，从而确定防止或下调IgE生成的方法。具体地说，我们将：1)确定有利于在体内产生抗原特异性IgE的条件；2)评估B细胞受体与其抗原在免疫球蛋白类开关上的亲和力的重要性；3)确定表达与IgE抗体相同的抗原特异性的非IgE抗体是否能够调节呼吸道的反应；以及4)确定T细胞是否参与了IgE反应的下调。我们相信，这些拟议的实验将增进我们对抗原反应中IgE产生的调节的了解，并将为特应性疾病的治疗开辟新的途径。

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.