RSV-INDUCED PATTERNS OF CYTOKINE EXPRESSION AND DISEASE

呼吸道合胞病毒（RSV）是引起呼吸道感染的重要原因。 这种疾病已经得到了疫苗开发的高度重视。 以前的候选疫苗在临床试验中失败了，福尔马林- 灭活明矾沉淀全病毒制剂与 疫苗增强的疾病 RSV亚单位疫苗处于临床前 在RSV血清阳性婴儿中进行的早期I期试验， 开始. 我们描述了一种研究RSV的BALB/c小鼠模型 免疫发病机制，最近获得的证据表明， 灭活RSV抗原诱导2型T辅助淋巴细胞（Th 2）模式 的细胞因子mRNA表达（优势IL-4表达），而引发 活RSV诱导Th 1样应答（IFN-γ显性表达） 在RSV攻击后的小鼠中。 发现最初的抗原引发 可导致选择性诱导免疫应答， 随后的鼻腔挑战，提出了一个新的和可检验的假设， RSV疫苗的发病机制会加剧疾病。 中有证据 选择性激活Th亚群的其它动物模型系统可 由免疫或感染引起，可影响疾病 结果。 最近研究表明，Th免疫或感染 并且可以影响疾病的结果。 最近的研究表明， 具有不同细胞因子分泌模式的淋巴细胞亚群 也可以在人体内找到。因此，我们建议利用老鼠 RSV模型，以确定免疫选择性 激活T细胞群和细胞因子表达模式。 我们将 鉴定肺中产生细胞因子mRNA的细胞的表型。 我们还将定义制剂、给药途径、剂量和 启动免疫的时间和细胞因子mRNA的模式 在肺中的表达和疾病的表达。 这项工作将增加我们的 对RSV疫苗免疫决定因素的一般理解- 增强的疾病可以确定将推进疫苗的开发， RSV和其他表面限制性病毒。

Respiratory syncytial virus (RSV) is an important cause of respiratory disease that has received high priority for vaccine development. Previous vaccine candidates have failed in clinical trials, and formalin- inactivated alum-precipitated whole virus preparation was associated with vaccine-enhanced illness. RSV subunit vaccines are in preclinical development and early phase I trials in RSV-seropositive infants have begun. We have described a BALB/c mouse model for the study of RSV immunopathogenesis, and have recently obtained evidence that priming with inactivated RSV antigen induces a type 2T helper lymphocyte (Th2) pattern of cytokine mRNA expression (dominant IL-4 expression), whereas priming with live RSV induces a Th1-like response (dominant IFN-gamma expression) in mice following RSV challenge. Finding that initial antigen priming can result in selective induction of immune responses following subsequent nasal challenge, suggests a new and testable hypothesis for the pathogenesis of RSV-vaccine enhance illness. There is evidence in other animal model systems that selective activation of Th subsets can be induced by immunization or infection and can influence disease outcome. It has recently been shown that Th immunization or infection and can influence disease outcome. It has recently been shown that Th lymphocyte subpopulations with distinct patterns of cytokine secretion can also be found in man. We therefore propose to utilize the mouse model of RSV to determine the mechanism by which immunization selectively activate T cell populations and patterns of cytokine expression. We will identify the phenotype of cells that produce the cytokine mRNA in lung. We will also define the correlation between formulation, route, dose, and timing of priming immunization and the pattern of cytokine mRNA expression in lung and expression of disease. This work will add to our general understanding of the immunologic determinants of RSV vaccine- enhanced disease can be identified will advance vaccine development for RSV and other surface-restricted viruses.