CYTOKINE MILIEU AND IMMUNE RESPONSE TO RSV

细胞因子环境和对 RSV 的免疫反应

• 批准号: 2442627
• 负责人: BARNEY S GRAHAM
• 金额: $ 29.14万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442627
• 关键词: antigen presentation; cytokine; cytotoxic T lymphocyte; disease /disorder model; enzyme linked immunosorbent assay; gene expression; genetically modified animals; helper T lymphocyte; human subject; immunity; laboratory mouse; polymerase chain reaction; respiratory syncytial virus; transfection /expression vector; vaccinia virus; vector vaccine

Development of a vaccine for respiratory syncytial virus (RSV) has received a high priority. The major impediment to initiating clinical trials with new candidate vaccines is an incomplete understanding of the vaccine-enhanced illness caused by formalin-inactivated RSV vaccines. Our group has described a BALB/c mouse model of RSV in which details of the immunologic mechanisms of RSV vaccine-immunopotentiation can be studied. We have shown that priming mice with inactivated RSV antigen induces a Th2-like cytokine mRNA expression pattern after RSV challenge (dominant IL-4 expression), and that live RSV priming by the nasal or parenteral route induces a Th1-like cytokine mRNA expression pattern after RSV challenge (dominant IFN-gamma expression). This finding has led us to propose the hypothesis that selective activation of the Th2 cell subset is responsible for RSV vaccine immunopotentiation of disease. The theme of this proposal is to address the impact of the cytokine milieu on the pattern of immune response to RSV immunization and challenge in both mice and humans. The specific aims are to: l) define the influence of the local and systemic cytokine environment on the response to RSV immunization and challenge in mice; 2) determine whether antigen specificity or mechanism of antigen presentation is the major factor in the selective activation of T cell subsets and pattern of cytokine expression in RSV-infected mice; and 3) test the validity of the mouse model by evaluating cytokine expression patterns in RSV-infected children. Aims l and 2 will be approached by using transgenic mice with "knock-outs" in specific cytokines, and recombinant vaccinia vectors that cc-express individual RSV proteins and specific murine cytokines. The human studies will take advantage of a clinical trial infrastructure for RSV therapeutics, and ongoing vaccine trials of live attenuated RSV to obtain serum, PBMC, nasal, and tracheal secretions for cytokine analysis. The assay detection methods for the human studies will include EIA for direct cytokine measurement, and quantitative RNA PCR for cytokine message. Validating the mouse as a model for evaluating patterns of immune response to RSV will accelerate preclinical development of candidate RSV vaccines. Defining how the cytokine milieu influences the immune response to RSV vaccination and challenge will impact strategies for RSV vaccine design and delivery.

呼吸道合胞病毒疫苗的研制 得到了高度优先的对待。启动临床的主要障碍 对新候选疫苗的试验是对 福尔马林灭活RSV疫苗引起的疫苗增强型疾病。我们的 小组描述了一种RSV的BALB/c小鼠模型，在该模型中， 可以研究RSV疫苗的免疫学机制--免疫增强。 我们已经证明，用灭活的RSV抗原免疫小鼠可以诱导一种 呼吸道合胞病毒攻击后Th2样细胞因子mRNA的表达模式(显性 IL-4表达)，以及通过鼻腔或肠外活体RSV启动 路径诱导RSV后Th1样细胞因子mRNA的表达 挑战(显性干扰素-γ表达)。这一发现使我们得以 提出Th2细胞亚群选择性激活的假设 负责呼吸道合胞病毒疫苗的免疫增强疾病。的主题 这项建议是为了解决细胞因子环境对 两种小鼠对RSV免疫和攻击的免疫应答模式 和人类。具体目的是：L)界定地方的影响力 和全身细胞因子环境对RSV免疫应答的影响 在小鼠中激发；2)确定抗原特异性或机制 抗原提呈是选择性激活的主要因素 呼吸道合胞病毒感染小鼠T细胞亚群及细胞因子表达模式； 3)通过评估细胞因子来检验小鼠模型的有效性 呼吸道合胞病毒感染儿童的表达模式。目标L和2将是 利用转基因小鼠在特定情况下进行“基因敲除” 细胞因子和cc表达个体RSV的重组痘苗病毒载体 蛋白质和特定的小鼠细胞因子。人体研究将需要 RSV疗法的临床试验基础设施的优势，以及 正在进行的RSV减毒活疫苗试验，以获得血清，PBMC， 鼻腔和气管分泌物用于细胞因子分析。化验检测 人体研究的方法将包括直接细胞因子的EIA 测量，以及细胞因子信息的定量RNA聚合酶链式反应。正在验证 小鼠作为评价RSV免疫应答模式的模型 加快RSV候选疫苗的临床前开发。定义如何 细胞因子环境影响RSV疫苗接种的免疫反应 挑战将影响RSV疫苗设计和交付的战略。