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: 8130787
• 负责人: Alessandro Sette
• 金额: $ 40.36万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130787
• 关键词: Algorithms; Alleles; Animal Model; Animals; Binding; Bioinformatics; Biological Assay; Biological Models; California; Categories; Cellular Immunity; Chinese People; 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）和食蟹猴（Macaca fascicularis）被广泛用作人类疾病发病机制的模型，并用于评价针对微生物病原体（包括新发疾病和潜在生物恐怖病原体）的疫苗和治疗剂。解释这些研究结果的能力受到准确定量其细胞免疫应答的有限能力的阻碍。该提案的重点是开发技术和工具，以评估中国恒河猴和食蟹猴的细胞介导的免疫。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，并通过鉴定拉沙病毒，马尔堡病毒和流感衍生表位来验证我们的方法。在具体目标1中，我们将定义五种常见的MHC I类分子的肽结合基序，每种分子来自食蟹猴和中国恒河猴。可用于实验研究的动物队列中常见A和B基因座MHC I类等位基因频率数据将由合作者提供，数据由内部生成。将为所研究的五种最频繁表达的MHC等位基因中的每一种产生稳定的转染子，从而允许可溶性MHC的产生和纯化。然后，我们将建立定量肽：MHC肽结合试验，并确定等位基因特异性MHC结合基序。该定量MHC：肽结合数据将用于算法开发。在具体目标2中，我们将开发并使MHC：肽预测算法可用于科学界。作为特定目标1的结果获得的大量结合数据将用于生成预测肽的MHC结合能力的算法。这些工具将允许快速预测来自任何感兴趣的A-C类病原体的潜在中国来源和食蟹猴表位。所有结合数据和算法将提交给免疫表位数据库，从而使这些工具免费提供给科学界。在具体目标3中，我们将在拉沙，马尔堡和流感病毒模型系统中实验验证我们的方法。我们将检测在特定目的1和2中进行的研究过程中鉴定的拉沙、马尔堡和流感病毒衍生表位的免疫原性。现在，由于我们的计算算法质量的改进，我们的努力不仅包括了最初提交的拉沙病毒，还包括了马尔堡和流感病毒。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病原体系统中的反应的表位。 项目叙述：恒河猴和食蟹猴被广泛用作人类疾病发病机制的模型，并用于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恐怖病原体。解释这些研究结果的能力受到准确定量其细胞免疫应答的有限能力的阻碍。该提案的重点是开发技术和工具，以评估这些动物模型中的细胞介导的免疫力。