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.

摘要 这一建议的中心假设是，有效疫苗和治疗性抗体的开发 将受益于仔细评估的所有潜在的保护或有害的抗病毒抗体 在临床前试验的所有阶段都有反应。小动物模型通常用于评估抗体- 基于干预措施提供绝育免疫，但这些模型也可能具有研究价值 病理学和保护机制超越中和。目前，雪貂（Mustela putorius furo）和 叙利亚仓鼠（Mesocricetus auratus）被认为是研究多种呼吸道疾病的良好小动物模型。 病原体既支持感染，表现疾病，又传播病毒。为了最佳地使用这些模型， 因此，迫切需要了解雪貂和仓鼠在重演中的适用性和/或不足， 影响人类临床结果的抗体效应子功能-需要对遗传学的基础研究 这些细胞中两种抗体以及Fc受体的多样性、表达模式和功能概况， 动物本项目的目标是在雪貂中进行初步的生物物理和功能Fc和FcR分析 和叙利亚仓鼠，以阐明影响物种特异性Fc-FcR依赖性效应子的关键变量 功能协调发展的实现这一目标是最佳翻译从新兴市场获得的见解的先决条件 保护性和治疗性小动物研究，以临床和人类临床的最佳优先战略 审判以强有力的初步数据为指导，并结合使用黄金标准和最先进的技术 在此基础上，通过两个具体目标的完成，实现项目目标：1）明确 Fc γ R和IgG之间的生物物理相互作用决定了雪貂和叙利亚 仓鼠，2）开发用于评估雪貂和仓鼠Fc介导的抗体的新型细胞系和测定 体外效应子功能。通过完成本提案的目标所获得的数据和结果将 因为它们将产生识别抗体和FcR的知识， 能够将免疫应答调节为有效的抗病毒活性而不是促进病理性 雪貂和仓鼠的炎症。这些知识将为有效翻译研究提供路线图 在这些小动物中进行，通常用于模拟呼吸道病原体，用于人体试验的结果。