MHC Analogy for Biodefense Animal Model Development

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战略中发挥着重要作用。疫苗的开发可能必须依赖于动物模型中的人类第一阶段安全性和疫苗效力数据(可能由非人类灵长类动物代表)，因为第二阶段效力试验可能是不可能的，缺乏(希望是)暴露和处于危险中的个人。准确和定量的免疫反应评估对于发展动物模型是至关重要的，这对于制定疫苗接种策略以及加深我们对疾病发病机制的理解至关重要。然而，系统地定义所使用的各种动物物种(以及人类)中的免疫优势抗原和表位是一项艰巨的任务，特别是当考虑到MHC多态的影响时。在本申请中，我们建议探索另一种方法。具体地说，我们将定义与表位特异性相关的猕猴(MAMU)MHC分子集，这些分子与最频繁出现的人类HLA分子高度重叠。在MHC结合水平上观察到的交叉反应与初级免疫原性的相关性将通过评估MHC类型猕猴和普通人类感染流感后特定表位的识别来检验。在非人类灵长类动物和人类中定义匹配的相似MHC分子集，将允许明智地使用MHC类型的猕猴，利用人类识别的相同表位来研究猕猴的免疫反应。这将增强猕猴模型与人类免疫反应的相关性。此外，这将提供测试基于表位的疫苗和诊断试剂的手段，这些疫苗和诊断试剂将用于非人类灵长类感染和疫苗接种模型。为了最大限度地覆盖一般人类种群和动物模型研究中使用的恒河猴种群，选择了通常以高频表达的分子进行研究。综上所述，这些研究将为利用猕猴动物模型研究人类高频表达的HLA抗原所限制的免疫反应提供一个独特的机会。

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.