IgG and FcR Characterization in Small Animal Models of RespiratoryDisease

摘要 这一提议的中心假设是有效疫苗和治疗性抗体的开发 将受益于对各种潜在的保护性或有害的抗病毒抗体的仔细评估 在临床前试验的所有阶段都有反应。小动物模型经常被用来评估抗体- 基于提供绝育免疫的干预措施，但这些模型也可能具有研究价值 超越中和的病理和保护机制。目前，雪貂(Mustela Putorius Furo)和 叙利亚仓鼠(Mesocrictus Auratus)被认为是研究各种呼吸道疾病的良好小型动物模型 病原体既支持感染，表现疾病，又传播病毒。为了更好地使用这些模型， 迫切需要了解雪貂和仓鼠在复述时的适宜性和/或不足 影响人类临床结果的抗体效应器功能-需要对遗传学进行基础研究 这些细胞中抗体和Fc受体的多样性、表达模式和功能 动物。这个项目的目标是在雪貂身上进行初步的生物物理和功能Fc和FCR特征分析 和叙利亚仓鼠一起阐明影响物种特异性Fc-FCR依赖效应器的关键变量 功能。实现这一目标是最佳翻译从新兴市场中获得的见解的先决条件 将保护性和治疗性小动物研究应用于临床，并为人类临床制定最优先的策略 审判。以强劲的初步数据为指导，使用黄金标准和最先进的组合 通过以下两个具体目标的完成，项目目标将得以实现：1)确定 决定雪貂和叙利亚人效应器功能的Fc、R和Ig G之间的生物物理相互作用 仓鼠，2)开发新的细胞系和用于评价雪貂和仓鼠Fc介导的抗体的方法 效应器在体外发挥作用。通过完成本提案的目标而获得的数据和结果如下 具有重大意义和创新性，因为它们将产生识别抗体和FCR的知识 能够将免疫反应调整为有效的抗病毒活性而不是促进病理变化的相互作用 雪貂和仓鼠的炎症。这些知识将为研究成果的有效翻译提供路线图 在这些经常被用来模拟呼吸道病原体的小动物身上进行的实验，会影响到人体试验的结果。

ABSTRACT The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies will benefit from careful evaluation of the full range of potentially protective or harmful antiviral antibody responses throughout all stages of preclinical testing. Small animal models are often used to assess antibody- based interventions to provide sterilizing immunity, but these models may also hold value for studying pathology and mechanisms of protection beyond neutralization. At present, ferrets (Mustela putorius furo) and Syrian hamsters (Mesocricetus auratus) are thought to be good small-animal models for diverse respiratory pathogens as both support infection, manifest disease, and transmit virus. To optimally use these models, there is a critical need to understand the suitability and/or shortfalls of ferrets and hamsters in recapitulating antibody effector functions that affect human clinical outcomes—requiring basic research into the genetic diversity, expression patterns, and functional profiles of both antibodies as well as Fc receptors in these animals. The goal of this project is to perform initial biophysical and functional Fc and FcR profiling in ferrets and Syrian hamsters to elucidate key variables that impact species-specific Fc-FcR-dependent effector functions. Achieving this goal is a prerequisite for optimal translation of insights gained from emerging protective and therapeutic small-animal studies to the clinic and to best prioritize strategies for human clinical trials. Guided by strong preliminary data, and using a combination of gold-standard and state-of-the art approaches, the project goal will be achieved though completion of two Specific Aims: 1) Define the biophysical interactions between FcR and IgG that determine effector functions in ferrets and Syrian hamsters, 2) Develop novel cell lines and assays for evaluating ferret and hamster Fc-mediated antibody effector functions in vitro. The data and results obtained by completing the aims of this proposal will be significant and innovative because they will generate knowledge that will identify the antibody and FcR interactions capable of tuning immune response towards potent antiviral activity versus promoting pathological inflammation in ferrets and hamsters. This knowledge will provide a roadmap for effective translation of studies performed in these small animals, often used to model respiratory pathogens, to outcomes in human trials.