Poxviruses: Defining Epitope Immunodominance

接种牛痘病毒可长期预防天花， 这是一种用于在全世界消除天花自然感染的方法。这是在没有详细的 了解人类T细胞对痘病毒的反应。由于担心使用天花病毒作为 一种生物武器，天花疫苗目前正在重新引入。考虑到相对较高的发病率 因此，开发一种更安全、更有效的疫苗非常重要。 牛痘病毒能激发强烈的细胞和体液免疫反应。细胞免疫似乎 对感染后的恢复更为重要疫苗接种的严重并发症与 先天性或获得性T细胞缺乏，但不伴有先天性无丙种球蛋白血症。存在 中和抗体单独不能阻止进行性牛痘的发展， 免疫力有缺陷。为了分析人类T细胞对许可和实验性天花的反应， 在单细胞水平上的疫苗，识别T细胞表位，特别是免疫显性CD8 T 细胞表位 牛痘是一种大型病毒，我们假设我们可以开发一种快速的方法来定位基因， 编码人T细胞表位的片段，并使用PCR产生的肽精确鉴定它们。 含有病毒基因的DNA片段转染到抗原呈递细胞中。互补 策略将采用肽库和在表达普通人类MHC的转基因小鼠中的研究 I类分子。将分析牛痘病毒上人T细胞表位的免疫优势。的 本研究的结果将为人类T细胞的基础研究提供有价值的信息 对实验性天花疫苗的设计和分析有用的记忆和数据。我们的方法 将在本项目中建立可能适用于其他大型病毒以及细菌的定义 人T细胞表位。

Immunization with vaccinia virus resulted in long-lasting protection against smallpox and was the approach used to eliminate natural smallpox infections worldwide. This was accomplished without a detailed understanding of human T cell responses to poxviruses. Due to concerns about the use of smallpox virus as a bioweapon, smallpox vaccination is currently being reintroduced. Considering the relatively high incidence of side effects, developing a safer, but effective vaccine is very important. Vaccinia virus elicits strong cellular as well as humoral immune responses. Cellular immunity seems to be more important for recovery from infection. Severe complications from vaccination were associated with congenital or acquired T cell deficiencies, but not with congenital agammaglobulinemia. The presence of neutralizing antibody alone did not prevent the development of progressive vaccinia if cell-mediated immunity was defective. In order to analyze human T cell responses to licensed and experimental smallpox vaccines at the single cell level, it is essential to identify T cell epitopes, especially immunodominant CD8 ¿ T cell epitopes. Vaccinia is a large virus and we hypothesize that we can develop a rapid approach to localize gene fragments encoding human T cell epitopes and to identify them precisely using peptides using PCRgenerated DNA fragments containing virus genes transfected into antigen presenting cells. Complementary strategies will employ peptide libraries and studies in transgenic mice expressing common human MHC class I molecules. The immunodominance of human T cell epitopes on vaccinia virus will be analyzed. The results of this research project will provide valuable information relative to basic studies of human T cell memory and data useful for the design and analyses of experimental smallpox vaccines. The methods we will establish in this project may be applicable to other large viruses as well as bacteria for the definition of human T cell epitopes.