MHC Analogy for Biodefense Animal Model Development

描述（由申请人提供）：动物模型在当前针对生物恐怖主义制剂的疫苗开发设想的策略中发挥着基础作用。疫苗开发可能必须依赖动物模型（可能以非人类灵长类动物为代表）中的人类一期安全性和疫苗功效数据，因为二期功效试验可能无法进行，因为缺乏（希望）暴露和高危个体。准确和定量的免疫反应评估对于动物模型的开发至关重要，这对于制定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，系统地定义各种动物物种（以及人类）的免疫显性抗原和表位是一项艰巨的任务，特别是当考虑到 MHC 多态性的影响时。在本申请中，我们建议探索一种替代方法。具体来说，我们将定义与表位特异性相关的猕猴 (Mamu) MHC 分子集，这些分子与最常见的人类 HLA 分子高度重叠。将通过评估 MHC 型猕猴和一般人群感染流感后特定表位的识别来测试在 MHC 结合水平和初级免疫原性上观察到的交叉反应的相关性。在非人类灵长类动物和人类中定义类似 MHC 分子的匹配组，将允许通过明智地使用 MHC 型猕猴，利用人类识别的相同表位来研究猕猴的免疫反应。这将增强人类免疫反应的猕猴模型的相关性。此外，这还将提供在非人类灵长类动物感染和疫苗接种模型中测试人类使用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，拟议的研究将为使用猕猴动物模型来研究受人类高频率表达的 HLA 抗原限制的免疫反应提供独特的机会。

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.