RSV INDUCED PATTERN OF CYTOKINE EXPRESSION AND DISEASE

呼吸道合胞病毒(RSV)是引起 婴儿严重的下呼吸道疾病，与之媲美 流感是我国死亡率和发病率过高的原因之一 老年人，并在骨髓移植单位造成流行病 在大多数情况下都是致命的。适当的治疗和 疫苗无法获得，部分原因是独特的 呼吸道合胞病毒所致疾病的免疫学特征。福尔马林灭活整体 病毒疫苗(FI-RSV)不能预防感染，因此 与增强的疾病相关。来自小鼠模型和证据的数据 来自人类的研究表明，选择性诱导CD4+T细胞 具有2型细胞因子表达模式的淋巴细胞(主要是IL-4 生产)FI-RSV疫苗是疫苗增强的基础 生病了。婴儿严重的呼吸道合胞病毒毛细支气管炎也与 2型免疫反应。这项建议的主要目标是 明确RSV促进相关免疫反应的机制 细胞因子产生的类型为2型。具体的施舍对象是： 1)确定RSV G糖蛋白促进 嗜酸性粒细胞增多症、Th2样免疫反应和疾病增强，以及2) 明确IL-4延迟病毒清除、抑制病毒的机制 CD8+CTL诱导，并促进增强RSV诱导的疾病。这个 RSV G独特的抗原性将用重组 表达膜锚定G、分泌G或 这两种产品的产量相同。我们将定义G结构的作用 IL-4非依赖性诱导IL-5的抗原处理事件 和最近在我们实验室发现的嗜酸性粒细胞。这一机制 IL-4对CD8+CTL诱导的抑制作用 我们实验室构建的重组痘苗病毒 共表达RSV M2蛋白和单个细胞因子。这个 拟议的研究将确定病毒和宿主因素 了解RSV后的免疫反应和疾病表现模式 感染。它们将提高我们对病毒如何 导致疾病，以及疫苗诱导的免疫反应是如何调节的， 将直接影响制定预防犯罪的新战略 呼吸道合胞病毒疫苗和免疫疗法。

Respiratory Syncytial Virus (RSV) is the most important cause of severe lower respiratory tract disease in infants, rivaling influenza as a cause of excess mortality and morbidity in the elderly, and causing epidemics in bone marrow transplant units with fatality in the majority of cases. Adequate therapy and vaccines are not available, in part because of the unique immunologic features of RSV-induced disease. Formalin-inactivated whole virus vaccine (FI-RSV) did not protect against Infection and was associated with enhanced disease. Data from murine models and evidence from human studies suggest that selective induction of CD4+ T lymphocytes with a Type 2 cytokine expression pattern (dominant IL-4 production) by the FI-RSV vaccine is the basis for vaccine-enhanced illness. Severe RSV bronchiolitis in infants is also associated with Type 2 immune responses. The primary objective of this proposal is to define the mechanisms by which RSV promotes immune responses associated with Type 2 pattern of cytokine production. The specific alms are to: 1) Define the mechanisms by which the RSV G glycoprotein promotes eosinophilia, Th2-like immune responses, and enhanced illness, and 2) Define the mechanisms by which IL-4 delays virus clearance, inhibits CD8+ CTL induction, and promotes enhanced RSV-induced illness. The unique antigenic properties of RSV G will be studied using recombinant vaccinia viruses that express membrane-anchored G, secreted G, or produce both in equal amounts. We will define the role of G structure and antigen processing events on the IL-4 independent induction of IL-5 and eosinophils recently discovered in our laboratory. The mechanism of IL-4 inhibition of CD8+ CTL induction will be defined using recombinant vaccinia viruses constructed in our laboratory that co-express the RSV M2 protein and individual cytokines. The proposed studies will define viral and host factors responsible for patterns of immune response and disease expression after RSV infection. They will improve our basic understanding of how viruses cause disease, and how vaccine-induced immune responses are regulated, will have direct impact on new strategies for development of preventive vaccines and immunotherapeutics for RSV.