Endogenous Adjuvants in Viral Immunity and Vaccines

病毒免疫和疫苗中的内源佐剂

• 批准号: 6711611
• 负责人: KENNETH L ROCK
• 金额: $ 44.21万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6711611
• 关键词: antigens; biological signal transduction; dendritic cells; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; host organism interaction; immune response; immunity; immunization; immunomodulators; laboratory mouse; lymphocytic choriomeningitis virus; microorganism immunology; model design /development; toll like receptor; urate; vaccine development; virus cytopathogenic effect; virus infection mechanism

The theme of project 1 is the characterization of a novel class of adjuvants and is based on our discovery that mammalian cells contain molecules with unique adjuvant properties that are released when cells are injured and alert the immune system to danger. Our underlying hypothesis is that these endogenous molecules normally play an important role in initiating immune responses to infections and can be exploited as a novel class of adjuvants for vaccines. The objectives of this project are to establish the molecular identify of these molecules, to elucidate their biological effects and underlying mechanisms of action, and to test their potential utility for vaccines for the class A biodefense pathogen, LCMV. An important aspect of these studies will be our interaction with projects #2 and #3 to examine whether the endogeous adjuvant works through Toll-like receptors (TLR) and/or whether various TLR agonists synergize with stimulation by the endogenous adjuvants. This project consists of three Aims. The first Aim will purify the major endogenous adjuvants and determine their molecular structure. The second Aim will elucidate the kinds of immune responses they enhance, determine how they compare to TLR agonists and evaluate whether these molecules are useful alone or in combination as vaccine adjuvants. The importance of this goal is that it will define what kinds of immune responses these adjuvants help to regulate and hence the settings in which they will be useful for enhancing vaccine efficacy. The third aim will elucidate the cellular and molecular mechanisms of the endogenous adjuvant activity. We will examine the hypothesis that they augment immune responses by acting on dendritic cells and define how dendritic cell function (or that of other cellular targets) is changed. We will also test the hypothesis that these adjuvant molecules signal through TLRs. In addition, we will compare the molecular changes induced by the endogenous adjuvants to those stimulated by microbial agonists of TLRs. Together these Aims and the ones of the other projects will provide insight into how infection with LCMV leads to immunity versus disease and identify novel classes of adjuvants for vaccine development.

项目1的主题是一类新型佐剂的表征，并且基于我们的发现，即哺乳动物细胞含有具有独特佐剂特性的分子，当细胞受伤时释放并警告免疫系统危险。我们的基本假设是，这些内源性分子通常在启动对感染的免疫应答中起重要作用，并且可以用作一类新型疫苗佐剂。该项目的目标是确定这些分子的分子鉴定，阐明其生物学效应和潜在的作用机制， 测试它们作为A类生物防御病原体LCMV疫苗的潜在效用。这些研究的一个重要方面将是我们与项目#2和#3的相互作用，以检查内源性佐剂是否通过Toll样受体（TLR）起作用和/或各种TLR激动剂是否与内源性佐剂的刺激协同作用。该项目包括三个目标。第一个目的是纯化主要的内源性佐剂并确定其分子结构。第二个目标将阐明它们增强的免疫应答的种类，确定它们如何与TLR激动剂进行比较，并评估这些分子是否单独或组合用作疫苗佐剂。这一目标的重要性在于， 确定这些佐剂有助于调节何种免疫反应，从而确定它们可用于增强疫苗效力的环境。第三个目标将阐明内源性佐剂活性的细胞和分子机制。我们将检验它们通过作用于树突状细胞来增强免疫反应的假设，并定义树突状细胞功能（或其他细胞靶点）是如何改变的。我们还将测试这些佐剂分子通过TLR信号传导的假设。此外，我们将比较内源性佐剂诱导的分子变化与TLR的微生物激动剂刺激的分子变化。这些目标和其他项目的目标一起将提供洞察力 研究LCMV感染如何导致对疾病的免疫力，并确定用于疫苗开发的新型佐剂。