Immunogenetic Mechanisms of Vaccine Response

本申请是R01 AI48793第6-10年的续期资金申请。我们的长期目标是 确定影响活病毒疫苗免疫反应的遗传机制，并回答 关于依赖于免疫遗传学的免疫反应的差异如何和程度的问题 决定用活病毒疫苗进行免疫的结果。因为它的核心作用 作为细胞间蛋白信使的细胞因子及其受体，在免疫反应级联反应中， 细胞因子和细胞因子受体基因多态性的作用将是这一研究的主要焦点 应用，我们将集中在这些多态对体液和细胞测量的影响 风疹病毒活疫苗-ASA模型的免疫应答研究 免疫遗传学对疫苗反应变异性的研究。为了实现这些目标，我们提出了以下建议 具体目标：1)检验特定基因的多态之间存在显著关联的假设 细胞因子基因(IFNA、(3，y、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12A、IL-12B、TNFa和GM-CSF)和风疹 免疫反应(中和抗体水平和细胞免疫标志物)，2)测试 特定细胞因子受体基因的多态之间存在显著相关性的假设 (IL-2RA、IL-2RB、IL-2RG、IL-4R、IL-6R、IL-6ST、IL-10RA、IL-10RB、IL-12RB1、IL-12RB2、IFNAR1、IFNAR2、 IFNGR1、IFNGR2、TNFRSF1A、TNFRSF1B、CSF2RA和CSF2RB)和风疹免疫反应，3)至 测试分泌的细胞因子蛋白水平之间存在显著关联的假设(IFNA，(3，y， IL-2、IL-4、IL-5、IL-6、IL-10、IL-12(p35和p40)、TNFa和GM-CSF 风疹免疫反应；4)验证I、II类人类白细胞抗原基因与风疹的关系 在我们之前的研究中发现的免疫反应，并评估基因-基因相互作用对 这些免疫反应在一个新的验证队列中。这项提议是创新的，因为它审查了影响 免疫遗传学对疫苗反应变异性的研究。这一信息的意义在于它将 为估计人类白细胞抗原变异性对免疫反应变异性的贡献提供了一个框架 并为开发新的病毒疫苗(艾滋病毒、人乳头瘤病毒、丙型肝炎和 其他)在遗传异质性的种群中。 与公共健康的相关性：这项拨款建议研究影响和决定 人体对风疹疫苗的免疫应答。从这些研究中获得的知识将使我们能够 设计新的战略和新的疫苗，以保护人类健康免受病毒疾病的侵害。

This application is for renewed funding for years 6-10 of R01 AI48793. Our long-term objective isto determine the genetic mechanisms influencing the immune response to live viral vaccines, and to answer the question of how and to what degree differences in immune responses that depend upon the immunogenetics of the individual determine the outcome of immunization with live viral vaccines. Because of the central role of cytokines as intercellular protein messengers, and their receptors, in the immune response cascade, the role of cytokine and cytokine receptor gene polymorphisms will be a primary focus of this application, and we will focus on the influence of these polymorphisms on measures of humoral and cellular immune response to a live viral vaccine - rubella - asa model with which to explore the influenceof immunogenetics on the variability of vaccine response. To accomplish these goals, we propose thefollowing specific aims: 1) To test_the hypothesis that significant associations exist between polymorphisms of specific cytokine genes (IFNa, (3, y, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12A, IL-12B, TNFa and GM-CSF) and rubella immune responses (neutralizing antibody level and markers of cell-mediated immunity), 2) To test the hypothesis that significant associations exist between polymorphisms of specific cytokine receptor genes (IL-2RA, IL-2RB, IL-2RG, IL-4R, IL-6R, IL-6ST, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, IFNAR1, IFNAR2, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, CSF2RA and CSF2RB), and rubella immune responses, 3) To test the hypothesis that significant associations exist between secreted cytokine protein levels (IFNa, (3, y, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p35 and p40), TNFa and GM-CSF) after ex vivo rubella stimulation and rubella immune responses, and 4) To verify the associations between class I and II HLA genes and rubella immune responses found in our previous study and to assess potential effects of gene-gene interactions on these immune responses within a new validation cohort. The proposal is innovative as it examines the effect of immunogenetics on variability of vaccine response. The significance of this information is that it will provide a framework for estimating the contribution of HLA variability on variability of immune responses as well as provide knowledge important to the development of new viral vaccines (HIV, HPV, Hepatitis C, and others) in a genetically heterogeneous population. Relevance to Public Health: This grant proposes to study the genes that influence and determine the human immune response to rubella vaccine. The knowledge gained from these studies will enable us to design new strategies and new vaccines to protect human health against viral diseases.