NUCLEIC ACID VACCINE AS PREVENTIVE AND THERAPEUTIC MODALITY

这个项目的发起是为了阐明一种新认识的 并延长我们对免疫反应和免疫的长期研究 丙型肝炎病毒感染的临床后遗症。其中一个 基因免疫的优点是内源性表达 蛋白质可以被I类MHC分子识别并表达在 细胞表面。细胞表面的MHC抗原复合体可以是 被细胞毒性T淋巴细胞(CTL)识别，然后被激活 攻击受感染的细胞。诱导免疫反应的可能性 为丙型肝炎病毒核心蛋白的DNA免疫提供了诱人的 传统疫苗接种的替代方案。有很多问题需要解决 与丙型肝炎疫苗的开发有关，主要关注的问题之一 是传染性病原体丙型肝炎病毒的遗传稳定性。有两个 推测的丙型肝炎病毒包膜蛋白中的高变区。免疫逃逸 观察到的突变归因于这些区域的突变。 实验感染的黑猩猩和丙型肝炎患者被发现患有 反复感染同源或新的丙型肝炎病毒株。 这也可能是80%以上的感染 变得慢性病。直接诱导强大的细胞免疫， 尤其是保护性细胞毒性T淋巴细胞，可能不仅有助于 预防最初的丙型肝炎病毒感染，但也可能产生免疫调节 以克服现有的感染。在过去的一年里，我们已经建造了 几种不同的含有丙型肝炎病毒基因的质粒，并能够评估 小鼠抗丙型肝炎病毒核心蛋白抗体的诱导。我们现在在 开发检测小鼠模型中CTL活性的方法的过程。

This program was initiated to elucidate a newly recognized modality of vaccination and to extend our long-term study of the immune response and clinical sequelae of hepatitis C virus (HCV) infection. One of the advantages of genetic immunization is that the endogenously expressed proteins can be recognized by class I MHC molecules and expressed on the cell surface. The MHC-antigen complex on the cell surface can be recognized by cytotoxic T lymphocytes (CTL), which in turn are activated and attack infected cells. The possibility of inducing an immune response to HCV core protein using DNA immunization provides an attractive alternative to classic vaccination. There are many problematic issues related to vaccine development for hepatitis C. One of the major concerns is the genetic stability of the infectious agent, HCV. There are two hypervariable regions in the putative HCV envelope proteins. Immune escape mutants observed were attributed to mutations in these regions. Experimentally infected chimpanzees and HCV patients were found to have repeated bouts of infection with either homologous or new strains of HCV. This-could also be one of the reasons that more than 80% of the infections become chronic. Directly inducing strong cell-mediated immunity, especially protective cytotoxic T lymphocyte, may not only help in preventing initial HCV infection, but may also produce immune modulation to overcome existing infection. During the past year, we have constructed several different plasmids containing HCV genes and were able to evaluate the induction of antibodies to HCV core proteins in mice. We are in the process of developing assays to measure CTL activity in the mouse model.