Transgenic Aminal Core

这个核心的目的是通过生成和维护动物模型来支持拟议的项目 用于体内研究，研究抗流感抗体在病毒感染期间如何调节宿主免疫。 动物核心的第一个目标将是保持转基因小鼠品系，供每个项目使用。我们的 最近的研究表明，Fc恒定区之间的相互作用广泛中和 抗体(BNAbs)和Fc受体(FCR)是最佳中和流感病毒所必需的 活着。然而，人(Hu)FCR系统在表达模式上与小鼠不同，其亲和力 每个人的免疫球蛋白Fc亚类对应于每个huFcR，以及哪些huFcRs和效应细胞在体内占主导地位。 因此，为了解决huFcRs在体内病毒中和过程中的功能贡献， 人类bNAbs，我们最近产生了FCR人源化的小鼠，它们表达了完整的huFcr 缺乏所有小鼠FCR的背景，并且具有诱导人免疫球蛋白介导的Fc反应的能力。 FcyR人源化小鼠概括了huFcyRs的独特表达谱，并功能介导 HulgG抗体在体内的炎症、免疫调节和细胞毒活性。这些动物将成为 对于研究人bNAbs在体内的中和作用，了解中和机制是至关重要的 体内，并研究通过操纵Fc-FCR相互作用来增强体内中和作用的方法。 该核心还将支持维护缺少特定FcIR的鼠标行和具有特定FcIR的行 在特定单元子集中有条件地删除FCR。这些小鼠品系将是支持研究的关键 研究bNAbs在体内中和病毒的机制，这一动物核心将支持 维护这些鼠线，以供本项目的所有研究人员使用。 小鼠被动注射hulgG bNAbs可产生抗HuIg G抗体，可清除人 BNab.这种对被动转移的人bNAb的清除排除了对人的长期活体研究 小鼠体内的bNAbs。因此，动物核心的第二个目标将是产生一个敲入小鼠品系 其中hulgGI恒定区取代了小鼠的lgG2a恒定区。因此，这只鼠标将表示 HulgGI是一种自身蛋白，对被动的人bNAb给药是耐受的。这条线将被跨越到 FCR人源化小鼠系，从而产生了一种优越的体内模型，在该模型中，长期研究 人Ig G bNAbs可以在人FCR效应器功能的背景下执行。

The purpose of this core is to support the proposed projects by generating and maintaining animal models for in vivo studies investigating how anti-influenza antibodies regulate host immunity during virus infection. The first aim of the animal core will be to maintain transgenic lines of mice for use by each project. Our recent studies have demonstrated that interactions between the Fc constant region of broadly neutralizing antibodies (bNAbs) and Fc receptors (FcRs) are required for optimal neutralization of influenza viruses in vivo. However, the human (hu) FcR system differs from that of mice in expression patterns, the affinities of each human IgG Fc subclass for each huFcR, and which huFcRs and effector cells dominate in vivo. Therefore, in order to address the functional contributions of huFcRs during in vivo viral neutralization with human bNAbs, we have recently generated FcR-humanized mice, which express the full array of huFcRs on a background lacking all mouse FcRs and with the capacity to elicit human IgG mediated Fc responses. FcyR-humanized mice recapitulate the unique expression profile of huFcyRs and function to mediate the inflammatory, immunomodulatory and cytotoxic activities of hulgG antibodies in vivo. These animals will be vital for investigating in vivo neutralization by human bNAbs, understanding the mechanism of neutralization in vivo, and investigating methods to enhance neutralization in vivo by manipulating Fc-FcR interactions. This core will also support the maintenance of mouse lines lacking specific FcIRs and lines in which specific FcR are conditionally deleted in specific cell subsets. These mouse strains will be crucial to support studies investigating the mechanisms by which bNAbs neutralize virus in vivo, and this animal core will support the maintenance of these mouse lines for use by all investigators in this project. Passive administration of hulgG bNAbs to mice results in an anti-huIgG response which clears the human bNAb. This clearance of passively-transferred human bNAb precludes long-term in vivo studies with human bNAbs in mice. Therefore, the second aim of the animal core will be to generate a knock-in mouse line in which the hulgGI constant region replaces the mouse lgG2a constant region. Thus, this mouse will express hulgGI as a self-protein and be tolerized to passive human bNAb administration. This line will be crossed to the FcR-humanized mouse line, thereby generating a superior in vivo model in which long-term studies of human IgG bNAbs can be performed in the context of human FcR effector function.