IGG CLASS AND FUNCTION OF ANTIPOLYSACCHARIDE ANTIBODIES

描述：抗多糖（PS）抗体（Ab）对宿主至关重要 防御被包裹的细菌 抗PS抗体的功能包括 补体结合和调理作用的细菌的摄取和杀死 吞噬细胞 哺乳动物IgG抗PS Ab反应延迟了个体发育， 最初的同种型限制（小鼠中为IgG 3，人中为IgG 2）。 这些抗体 如果PS与蛋白质缀合，则主要转换为IgG 1， 小鼠和人。定义这种同种型限制的原因，以及 作为不同IgG亚类的抗PS抗体的相对功能 对于更好地理解对PS包裹的细菌的免疫至关重要， 人类疾病如IgG亚类缺乏症的发病机制。 精确 还评估了亚类对抗PS抗体功能的影响， 重要的是提高免疫接种后的血清学相关性 PS和PS结合疫苗。 不同来源抗PS抗体的功能 IgG亚类仍然不清楚，因为以前的研究使用 暴露于改变Fc的离液剂的多克隆亲和纯化的Ab 功能 此外，使用具有不同抗原性的单克隆抗体， 特异性，以及缺乏IgG亚类缺陷的动物模型， 限制了对亚类特异性抗体的理解。 在当前 建议研究者将精确定义IgG亚类的作用， 抗PS抗体的效应子功能，并确定恒定区的作用 在免疫和类中占优势的抗PS IgG亚类的基因 当PS与蛋白质结合时发生的转换。 首先利用 所有四种人源抗体的可变区相同的小鼠/人嵌合Ab 针对铜绿假单胞菌（PA）LPS O-侧链的亚类，研究者 将确定Ab在以下动物模型中的保护功效差异： PA感染，然后定义所观察到的功能性的机制， 差异 第二，他将制造和表征小鼠/人类嵌合体， 抗肺炎球菌荚膜PS抗体，以更好地确定IgG的作用 亚类，以改善血清学 保护的相关性，并确定抗PS亚类功能 差异是表位特异性的。 第三，为了确定体内 主要抗PS IgG亚类的重要性，并确定 重链基因在抗PS类别转换中的重要性， 研究人员和他的合作者已经成功地开发了一种IgG 3-通过3个基因靶向和同源的缺陷敲除小鼠 重组 现在将评估这些小鼠的免疫能力， 对PS、PS-蛋白缀合物和包囊细菌感染有反应。 这些研究将确定哪种抗PS IgG亚类功能最强 有效地对抗PS包被的细菌，更好地定义 IgG亚类之间的功能差异，并探讨 这些差异在体内。 这些数据将允许更理性的策略 对PS包被细菌的主动和被动免疫， 治疗IgG亚类缺陷。

DESCRIPTION: Anti-polysaccharide (PS) antibodies (Ab) are critical to host defense against encapsulated bacteria. The function of anti-PS Ab includes complement fixation and opsonization of bacteria for uptake and killing by phagocytes. The mammalian IgG anti-PS Ab response has delayed ontogeny and isotype restriction initially (IgG3 in mice, IgG2 in man). These antibodies class-switch predominately to IgG1 if the PS is conjugated to protein in both mouse and man. Defining the causes of this isotype restriction as well as the relative function of anti-PS antibodies of different IgG subclasses is crucial to better understanding immunity to PS-encapsulated bacteria and pathogenesis of human diseases such as IgG subclass deficiency. Precise evaluation of the effect of subclass on anti-PS antibody function is also important to improve serological correlates of immunity after vaccination with PS and PS-conjugate vaccines. The function of anti-PS Ab of different IgG subclasses remains unclear because to previous studies have used polyclonal affinity purified Ab exposed to chaotropic agents that alter Fc function. In addition, the use of monoclonal Ab with different antigenic specificities, and the lack of animal models of IgG subclass deficiency have limited the understanding of subclass-specific antibodies. In the current proposal the investigator will precisely define the role of IgG subclass in anti-PS Ab effector function, and determine the role of the constant region gene for the dominant anti-PS IgG subclass in immunity and in class switching that occurs when PS are conjugated to proteins. First, using variable region identical mouse/human chimeric Ab of all four human subclasses against P. aeruginosa (PA) LPS O-side chain, the investigator will determine differences in protective efficacy of Ab in animal models of PA infection and then define the mechanism of the observed functional differences. Second, he will make and characterize mouse/human chimeric antibodies against pneumococcal capsular PS to better define the role of IgG subclass in protection against pneumococcus, to improve serological correlates of protection and to determine if anti-PS subclass functional differences are epitope specific. Third, in order to determine the in vivo importance of the predominant anti-PS IgG subclass and to determine the importance of the heavy chain gene in anti-PS class switching, the investigator and his collaborators have successfully developed an IgG 3-deficient knockout mouse via 3 gene targeting and homologous recombination. These mice will now be evaluated for their ability to immunologically respond to PS, PS-protein conjugates, and encapsulated bacterial infections. These studies will determine which anti-PS IgG subclass functions most efficiently against PS-coated bacteria, better define the mechanism of functional differences between IgG subclasses and explore the relevance of these differences in vivo. These data will allow more rational strategies of active and passive immunization against PS-coated bacteria and improved treatment of IgG subclass deficiencies.