RSV-INDUCED PATTERNS OF CYTOKINE EXPRESSION AND DISEASE

呼吸道合胞病毒(RSV)是引起呼吸道疾病的重要原因 已被列为疫苗开发高度优先事项的疾病。 之前的候选疫苗在临床试验中都失败了，福尔马林- 灭活明矾沉淀全病毒制剂与 疫苗强化的疾病。呼吸道合胞病毒亚单位疫苗处于临床前 RSV血清阳性婴儿的发育和早期I期试验 开始了。我们建立了一种研究呼吸道合胞病毒的BALB/c小鼠模型。 免疫致病机制，最近有证据表明，用 灭活RSV抗原诱导型2T辅助淋巴细胞(Th2)模式 细胞因子mRNA的表达(主导的IL-4表达)，而启动 与活的RSV一起诱导Th1样反应(主导的干扰素-γ表达) 在RSV攻击后的小鼠中。发现最初的抗原启动 可导致以下免疫反应的选择性诱导 随后的鼻部挑战，提出了一个新的、可验证的假说 RSV疫苗的致病机理增强了疾病。有证据表明 选择性激活Th亚群的其他动物模型系统可以 由免疫或感染引起的，并能影响疾病 结果。最近有研究表明，Th免疫或感染 并会影响疾病的结局。最近有研究表明，Th 具有不同细胞因子分泌模式的淋巴细胞亚群 在人类身上也可以找到。因此，我们建议利用鼠标 RSV模型用于确定选择性免疫的机制 激活T细胞群和细胞因子的表达模式。我们会 确定在肺中产生细胞因子mRNA的细胞的表型。 我们还将定义配方、路线、剂量和 免疫时机与细胞因子基因表达模式的关系 肺组织的表达和疾病的表达。这项工作将增加我们的 对RSV疫苗免疫学决定因素的一般了解- 可以识别出增强的疾病将促进疫苗的开发 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.