The Immunogenetics of Macaques Used in Biodefense Research

用于生物防御研究的猕猴免疫遗传学

• 批准号: 7380154
• 负责人: Alessandro Sette
• 金额: $ 41.18万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-24 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380154
• 关键词: Algorithms; Alleles; Animal Model; Animals; Binding; Bioinformatics; Biological Assay; Biological Models; California; Categories; Cellular Immunity; Chinese People; Class; Collaborations; Communities; Computational algorithm; Data; Databases; Development; Disease; Disease model; Epitopes; Evaluation; Frankfurt-Marburg Syndrome Virus; Gene Frequency; Genome; Histocompatibility; Housing; Human; Immune; Immune response; Immunity; Immunogenetics; Influenza; Laboratories; Lassa virus; Macaca; Macaca fascicularis; Macaca mulatta; Monitor; New Mexico; Pathogenesis; Peptides; Primates; Production; Research; Research Personnel; System; Technology; Testing; Universities; Virus; Wisconsin; biodefense; cohort; immunogenicity; influenzavirus; interest; microbial; nonhuman primate; pathogen; research study; response; therapeutic vaccine; tool

DESCRIPTION (provided by applicant): Rhesus macaques (Macaca mulatta) and Cynomolgus macaques (Macaca fascicularis), are widely used as models of disease pathogenesis in humans and for evaluating vaccines and therapeutics against microbial pathogens, including emerging diseases and potential bioterror pathogens. The ability to interpret the results of these studies is hampered by a limited capacity to accurately quantitate their cellular immune responses. This proposal is focused on developing technology and tools to evaluate cell-mediated immunity in Chinese-origin rhesus macaques and Cynomolgus macaques. Our strategy relies on the identification of common major histocompatibility (MHC) class I alleles, determining their peptide binding motifs, developing bioinformatic tools to predict MHC:peptide interactions, and validating our approach by the identification of Lassa virus, Marburg virus and influenza-derived epitopes. In Specific Aim 1, we will define peptide binding motifs for five common MHC class I molecules each from Cynomolgus macaques and Chinese rhesus macaques. Common A and B loci MHC class I allele frequency data in animal cohorts available for use in experimental research will be provided by collaborators and data generated in-house. A stable transfectant will be produced for each of the five most frequently expressed MHC allele studied, allowing the production and purification of soluble MHC. We will then establish quantitative peptide:MHC peptide binding assays and determine allele specific MHC binding motifs. This quantitative MHC:peptide binding data will be used for algorithm development. In Specific Aim 2, we will develop and make MHC:peptide prediction algorithms available to the scientific community. The large amount of binding data obtained as a result of Specific Aim 1 will be utilized to generate algorithms to predict the MHC binding capacity of peptides. These tools will permit rapid predictions of potential Chinese-origin and Cynomolgus macaque epitopes from any Category A-C pathogen of interest. All binding data and algorithms will be submitted to the Immune Epitope Database, thereby making these tools freely available to the scientific community. In Specific Aim 3, we will experimentally validate our approach in the Lassa, Marburg and influenza virus model systems. We will test the immunogenicity of epitopes derived from Lassa, Marburg and influenza viruses identified in the course of the studies performed in Specific Aim 1 and 2. We now extended our efforts to encompass not only Lassa virus, as proposed in the original submission, but also Marburg and influenza viruses due to improvements in the quality of our computational algorithms. These studies will be performed in collaboration with collaborators. These experiments will validate the approach and tools developed and also identify epitopes that can be utilized to monitor responses in these A-C pathogen systems. Project Narrative: Rhesus macaques and Cynomolgus macaques are widely used as models of disease pathogenesis in humans and for evaluating vaccines and therapeutics against microbial pathogens, including emerging diseases and potential bioterror pathogens. The ability to interpret the results of these studies is hampered by a limited capacity to accurately quantitate their cellular immune responses. This proposal is focused on developing technology and tools to evaluate cell-mediated immunity in these animal models.

描述（由申请人提供）：恒河猴（Macaca mulatta）和cynomolgus猕猴（Macaca fascicularis）被广泛用作人类中疾病发病机理的模型，并评估针对微生物病原体的疫苗和治疗剂，包括新兴疾病，包括出现的生物疾病和潜在的生物疾病。解释这些研究结果的能力受到有限的能力准确量化其细胞免疫反应的能力。该提案的重点是开发技术和工具，以评估细胞介导的中国 - 原生恒河猕猴和cynomolgus猕猴的免疫力。我们的策略依赖于鉴定常见的主要组织相容性（MHC）I类等位基因，确定其肽结合基序，开发生物信息学工具来预测MHC：肽相互作用，并通过鉴定LASSA病毒，Marburg Virus和Marburg Virus和Inflaceza衍生的源自源自的效果来验证我们的方法。在特定的目标1中，我们将针对五个常见的MHC I类分子定义肽结合基序，分别来自Cynomolgus猕猴和中国恒河猕猴。共同的A和B基因座MHC I类等位基因频率数据可用于实验研究的动物同类群体，并将由合作者和内部生成的数据提供。研究的五个最常见的MHC等位基因中的每一个都将产生稳定的转运剂，从而允许生产和纯化可溶性MHC。然后，我们将建立定量肽：MHC肽结合测定，并确定特异性MHC结合基序。此定量MHC：肽结合数据将用于算法开发。在特定目标2中，我们将开发和制造MHC：科学界可用的肽预测算法。由于特定目标1获得的大量结合数据将用于生成算法来预测肽的MHC结合能力。这些工具将允许快速预测来自任何感兴趣的A-C病原体的潜在中国 - 猕猴猕猴表位。所有绑定数据和算法将提交给免疫表位数据库，从而使这些工具可自由使用。在特定目标3中，我们将在LASSA，MARBURG和HASSA病毒模型系统中实验验证我们的方法。我们将测试来自Lassa，Marburg和流感病毒的表位的免疫原性。在特定目标1和2中进行的研究过程中鉴定出来的。我们现在扩大了我们的努力，不仅涵盖了原始提议中的LASSA病毒，而且由于Marburg和Marburg和Marburg和Infelenza Viruse而在我们的计算机上提高了我们的计算型Algorith的质量。这些研究将与合作者合作进行。这些实验将验证开发的方法和工具，并确定可用于监测这些A-C病原体系统中反应的表位。 项目叙述：猕猴和膀胱猕猴被广泛用作人类疾病发病机理的模型，并评估针对微生物病原体的疫苗和治疗剂，包括新兴疾病和潜在的生物异常病原体。解释这些研究结果的能力受到有限的能力准确量化其细胞免疫反应的能力。该建议的重点是开发技术和工具，以评估这些动物模型中细胞介导的免疫力。