Immunogenetic Mechanisms of Vaccine Response

描述（由申请人提供）：本申请是为R 01 AI 48793的第6-10年重新提供资金。我们的长期目标是确定影响活病毒疫苗免疫应答的遗传机制，并回答依赖于个体免疫遗传学的免疫应答差异如何以及在多大程度上决定活病毒疫苗免疫结果的问题。由于细胞因子作为细胞间蛋白信使及其受体在免疫应答级联中的中心作用，细胞因子和细胞因子受体基因多态性的作用将是本申请的主要焦点，并且我们将集中于这些多态性对体液和细胞免疫应答的测量的影响，所述体液和细胞免疫应答是对活病毒疫苗-风疹-作为一个模型，探讨免疫遗传学对疫苗反应的变异性的影响。为实现这些目标，我们提出以下具体目标：1）验证特定细胞因子基因多态性之间存在显著关联的假设（IFN α、β、γ、IL-2、IL-4、IL-5、IL-6、IL-10、IL-12 A、IL-12 B、TNF α和GM-CSF）和风疹免疫应答（中和抗体水平和细胞免疫标志物）; 2）验证特异性细胞因子受体基因多态性与细胞免疫功能相关性的假设（IL-2 RA、IL-2 RB、IL-2 RG、IL-4 R、IL-6 R、IL-6ST、IL-10 RA、IL-10 RB、IL-12 RB 1、IL-12 RB 2、IFNAR 1、IFNAR 2、IFNGR 1、IFNGR 2、TNFRSF 1A、TNFRSF 1B、CSF 2 RA和CSF 2 RB）和风疹免疫应答，3）检验分泌的细胞因子蛋白水平之间存在显著关联的假设（IFN α，β，γ，IL-2，IL-4，IL-5，IL-6，IL-10，IL-12（p35和p40），TNF α和GM-CSF），和4）为了验证我们先前研究中发现的I类和II类HLA基因与风疹免疫应答之间的相关性，并评估基因-基因相互作用对这些免疫应答的影响。该应用程序是创新的，因为它检查了免疫遗传学对疫苗反应变异性的影响。这些信息的重要性在于，它将提供一个框架，用于估计HLA变异性对免疫应答变异性的贡献，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：该补助金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.