MHC Analogy for Biodefense Animal Model Development

生物防御动物模型开发的 MHC 类比

• 批准号: 6897721
• 负责人: Bianca Romina Mothe
• 金额: $ 18.5万
• 依托单位: CALIFORNIA STATE UNIVERSITY SAN MARCOS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-15 至 2008-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897721
• 关键词: Macaca mulatta; biological models; bioterrorism /chemical warfare; clinical research; epitope mapping; histocompatibility antigens; human subject; immune response; immunogenetics; major histocompatibility complex; model design /development; vaccine development

DESCRIPTION (provided by applicant): Animal models play a fundamental role in the strategy currently envisioned for vaccine development against bioterrorism agents. Vaccine development may have to rely on human Phase I safety and vaccine efficacy data in animal models (likely to be represented by non-human primates) as Phase II efficacy trials may not be possible, lacking (hopefully) exposed and at-risk individuals. Accurate and quantitative assessment of immune responses is essential for the development of animal models, which are crucial to devising vaccination strategies as well as enhancing our understanding of disease pathogenesis. To systematically define immunodominant antigens and epitopes in the various animal species utilized (and in humans as well) is, however, a daunting task, especially when the impact of MHC polymorphism is taken into account. In the present application, we propose exploring an alternative approach. Specifically, we will define sets of macaque (Mamu) MHC molecules associated with epitope specificities that are highly overlapping with the most frequently occurring human HLA molecules. The relevance of the cross-reaction observed at the level of MHC binding and primary immunogenicity will be tested by evaluating the recognition of specific epitopes following influenza infection in MHC-typed macaques and the general human population. Definition of matching sets of analogous MHC molecules in non-human primates and humans would allow, by judicious use of MHC-typed macaques, to study immune responses in macaques utilizing the same epitopes recognized by humans. This will enhance the relevance of macaque models of human immune responses. Additionally, this will provide the means for testing epitope-based vaccines and diagnostic reagents destined for human use in non-human primate models of infection and vaccination. To maximize coverage of the general human population and of the populations of rhesus macaques utilized in animal model studies, molecules commonly expressed in high frequencies have been selected for study. In conclusion, the proposed studies will provide a unique opportunity to use macaque animal models for the study of immune responses restricted by HLA antigens expressed with high frequency in humans.

描述（由申请人提供）：动物模型在目前设想的针对生物恐怖主义制剂的疫苗开发策略中发挥着重要作用。疫苗开发可能必须依赖于动物模型（可能以非人灵长类动物为代表）中的人类I期安全性和疫苗有效性数据，因为II期有效性试验可能不可能，缺乏（希望）暴露和风险个体。准确和定量评估免疫应答对于动物模型的开发至关重要，这对于设计疫苗接种策略以及增强我们对疾病发病机制的理解至关重要。然而，要系统地定义免疫显性抗原和表位在各种动物物种中使用（以及在人类中），是一项艰巨的任务，特别是当考虑到MHC多态性的影响。在本申请中，我们提出探索替代方法。具体而言，我们将定义与最常见的人类HLA分子高度重叠的表位特异性相关的猕猴（Mamu）MHC分子集。将通过评价MHC型猕猴和一般人群中流感病毒感染后特异性表位的识别，检测在MHC结合水平和初级免疫原性水平观察到的交叉反应的相关性。通过明智地使用MHC型猕猴，在非人灵长类动物和人类中定义类似MHC分子的匹配集合将允许研究猕猴中利用人类识别的相同表位的免疫应答。这将增强人类免疫反应的猕猴模型的相关性。此外，这将提供用于在非人灵长类动物感染和疫苗接种模型中测试预定用于人的基于表位的疫苗和诊断试剂的方法。为了最大限度地覆盖一般人群和动物模型研究中使用的恒河猴群体，选择了通常以高频率表达的分子进行研究。总之，所提出的研究将提供一个独特的机会，使用猕猴动物模型的研究免疫反应限制的HLA抗原表达频率高的人。