IgG and FcR Characterization in Small Animal Models of RespiratoryDisease

呼吸道疾病小动物模型中的 IgG 和 FcR 表征

• 批准号: 10678229
• 负责人: Margaret E Ackerman
• 金额: $ 25.07万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678229
• 关键词: 2019-nCoV; Achievement; Active Immunization; Address; Affect; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigen-Antibody Complex; Antigens; Architecture; Basic Science; Biocompatible Materials; Biological; Biology; Biophysics; Cell Line; Cells; Cellular Assay; Characteristics; Clinic; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Effector Cell; Evaluation; Fc Receptor; Fc domain; Ferrets; Genetic; Genetic Variation; Goals; Hamsters; Health; Human; Immune; Immune response; Immunity; Immunoglobulin G; In Vitro; Infection; Inflammation; Influenza; Intervention; Knowledge; Macaca mulatta; Measures; Mediating; Mesocricetus auratus; Modeling; Mus; Mustela putorius furo; Natural Killer Cells; Outcome; Passive Immunization; Pathologic; Pathology; Pattern; Pattern recognition receptor; Phagocytosis; Pre-Clinical Model; Preclinical Testing; Prevention strategy; Property; Research; Respiratory System; Respiratory Tract Infections; Rewards; Risk; Role; Safety; Seasons; Testing; Therapeutic; Therapeutic antibodies; Translating; Translations; Vaccines; Viral; Viral Antibodies; Viral Physiology; Virus; Virus Diseases; Work; animal model development; antibody-dependent cell cytotoxicity; biophysical analysis; experience; immune activation; immunogenicity; improved; in vitro Assay; in vivo; innovation; insight; monocyte; nonhuman primate; novel; pandemic disease; pathogen; pre-clinical; receptor; receptor binding; research and development; respiratory pathogen; response; stable cell line; tool; translational study; transmission process; treatment strategy; vaccine-induced antibodies; viral transmission

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.

抽象的 该提案的中心假设是开发有效的疫苗和治疗性抗体 将受益于对各种潜在有害的保护性或有害的抗病毒抗体的仔细评估 小动物模型通常用于评估抗体。 基于干预措施来提供灭菌免疫力，但这些模型也可能具有研究价值 病理学和超越中和的保护机制目前，雪貂（Mustela putorius Furo）和 叙利亚仓鼠（Mesocricetus auratus）被认为是多种呼吸系统的良好小动物模型 病原体既支持感染、表现疾病又传播病毒。 迫切需要了解雪貂和仓鼠在概括中的适用性和/或不足 影响人类临床结果的抗体效应功能——需要对遗传进行基础研究 这些抗体和 Fc 受体的多样性、表达模式和功能特征 该项目的目标是对雪貂进行初步的生物物理和功能性 Fc 和 FcR 分析。 和叙利亚仓鼠阐明影响物种特异性 Fc-FcR 依赖性效应器的关键变量 实现这一目标是对从新兴领域获得的见解进行最佳转化的先决条件。 临床保护性和治疗性小动物研究以及人类临床的最佳优先策略 以强有力的初步数据为指导，并结合黄金标准和最先进的技术。 方法，项目目标将通过完成两个具体目标来实现： 1) 定义 FcR 和 IgG 之间的生物物理相互作用决定了雪貂和叙利亚的效应器功能 仓鼠，2) 开发新的细胞系测定和抗体，用于评估雪貂和仓鼠 Fc 介导的 通过完成本提案的目标而获得的数据和结果将是体外效应器功能。 意义重大且具有创新性，因为它们将产生识别抗体和 FcR 的知识 能够调整免疫反应以获得有效的抗病毒活性而不是促进病理的相互作用 这些知识将为研究的有效转化提供路线图。 在这些小动物身上进行的实验，通常用于模拟呼吸道病原体，以达到人体试验的结果。