Immunogenetic Mechanisms of Vaccine Response

说明（由申请人提供）：此申请为R01 AI48793第6-10学年的续期申请。我们的长期目标是确定影响对活病毒疫苗免疫反应的遗传机制，并回答依赖于个体免疫遗传学的免疫反应差异如何以及在多大程度上决定使用活病毒疫苗免疫的结果的问题。由于细胞因子作为细胞间蛋白信使及其受体在免疫反应级联中的核心作用，细胞因子和细胞因子受体基因多态性的作用将是该应用的主要焦点，我们将重点研究这些多态性对风疹活病毒疫苗的体液和细胞免疫反应的影响，作为探索免疫遗传学对疫苗反应变异性的影响的模型。为实现这些目标，我们提出以下具体目标：1)验证特异性细胞因子基因（IFNa、（3、y、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12A、IL-12B、TNFa和GM-CSF）多态性与风疹免疫应答（中和抗体水平和细胞介导免疫标志物）之间存在显著相关性的假设；2）验证特异性细胞因子受体基因(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)与风疹免疫应答之间存在显著相关性。3)验证离体风疹刺激后分泌的细胞因子蛋白(IFNa、（3、y、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12（p35和p40）、TNFa和GM-CSF）水平与风疹免疫应答之间存在显著相关性的假设。4)验证我们之前研究中发现的I类和II类HLA基因与风疹免疫反应之间的关系，并在一个新的验证队列中评估基因-基因相互作用对这些免疫反应的潜在影响。该应用具有创新性，因为它检查了免疫遗传学对疫苗反应变异性的影响。这一信息的重要意义在于，它将为估计HLA变异对免疫反应变异的贡献提供一个框架，并为在遗传异质性人群中开发新的病毒疫苗（HIV、HPV、丙型肝炎等）提供重要知识。与公共卫生的相关性：这项拨款建议研究影响和决定人类对风疹疫苗免疫反应的基因。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性疾病的侵害。

DESCRIPTION (provided by applicant): This application is for renewed funding for years 6-10 of R01 AI48793. Our long-term objective is to 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 depends 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 - as a model with which to explore the influence of immunogenetics on the variability of vaccine response. To accomplish these goals, we propose the following 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 application 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 significant 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.