Transgenic Aminal Core

该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 用于研究抗流感抗体在病毒感染期间如何调节宿主免疫力的体内研究。 动物核心的第一个目标是维持转基因小鼠品系，供每个项目使用。我们 最近的研究表明，广泛中和的Fc恒定区之间的相互作用 抗体（bNAb）和Fc受体（FcR）是流感病毒在体内的最佳中和所必需的。 vivo.然而，人（hu）FcR系统与小鼠的FcR系统在表达模式、人（hu）FcR系统与小鼠的FcR系统的亲和力、人（hu）FcR系统的亲和力 每个huFcR的每个人IgG Fc亚类，以及哪些huFcR和效应细胞在体内占主导地位。 因此，为了解决huFcR在体内病毒中和过程中的功能贡献， 我们最近产生了FcR人源化小鼠，其在人bNAb上表达huFcR的完整阵列。 缺乏所有小鼠FcR的背景，并具有引发人IgG介导的Fc应答的能力。 Fc γ R人源化小鼠重现了huFc γ R的独特表达谱，并具有介导人源化的功能。 hulgG抗体在体内的炎性、免疫调节和细胞毒性活性。这些动物将 对于研究人bNAb的体内中和作用，了解中和作用的机制至关重要 在体内，并研究通过操纵Fc-FcR相互作用来增强体内中和的方法。 该核心还将支持缺乏特异性FcIR的小鼠品系和其中特异性FcIR存在的品系的维持。 FcR在特定的细胞亚群中有条件地缺失。这些小鼠品系将对支持研究至关重要 研究bNAbs在体内中和病毒的机制，这个动物核心将支持 维护这些小鼠品系，供本项目的所有研究者使用。 对小鼠被动施用huIgG bNAb导致抗huIgG应答，其清除了人抗体。 bNAb。这种被动转移的人bNAb的清除排除了人bNAb的长期体内研究。 小鼠中的bNAb。因此，动物核心的第二个目的将是产生敲入小鼠品系， 其中huIgG 1恒定区替代小鼠IgG 2a恒定区。因此，这只老鼠会表达 huIgGl作为自身蛋白，并耐受被动的人bNAb给药。这条线将被跨越， FcR-人源化小鼠系，从而产生上级体内模型，在该模型中， 可以在人FcR效应子功能的背景下进行人IgG bNAb的表达。

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.