EPITHELIAL CELLS AS MUCOSAL ADJUVANT FOR LIFE LONG IMMUNITY

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 SIV疫苗研究产生的大量数据表明，艾滋病毒疫苗是可以实现的。在病毒传播的初始阶段，粘膜组织中的体液和细胞免疫应答阻断或抑制复制的能力可能对接种疫苗的宿主抵抗感染的能力产生深远影响。开发一种有效的疫苗，限制病毒在粘膜入口复制可能是我们控制HIV感染的最大希望。我们认为，成功的疫苗有两个必要的特征：1）用病毒抗原终身刺激免疫系统; 2）在HIV初次复制部位产生靶向免疫应答。同时解决这两个问题的疫苗方法将有可能实现稳固的长期保护。为了满足这些要求，我们提出了一种替代方法，成功地将疫苗递送到粘膜部位并引发保护性粘膜免疫应答。我们建议使用上皮干细胞作为病毒抗原的永久来源，并将其分化的后代作为抗原产生呈递细胞。因此，目标是：1）研究将仅在终末分化的上皮细胞中表达的最佳启动子;和2）在通过皮肤、阴道和直肠途径接种的恒河猴中，从终末分化的角质形成细胞特异性启动子引发SIV抗原表达。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The significant amount of data generated by SIV vaccine studies has led to the suggestion that an HIV vaccine is achievable. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection. The development of an effective vaccine that restricts viral replication at the mucosal portal of entry may be our best hope for controlling HIV infection. We believe there are two necessary features for a successful vaccine: 1) life-long stimulation of the immune system with viral antigens; and 2) a targeted immune response at the site of primary replication of HIV. A vaccine approach that simultaneously addresses these two issues would have the potential to achieve solid, long-term protection. To fulfill these requirements, we propose an alternative approach to successfully deliver a vaccine to mucosal sites and elicit protective mucosal immune responses. We propose to use the epithelial stem cell as a permanent source of viral antigen and their differentiated offspring as antigen producing presenting cells. Therefore, the goal is: 1) To investigate the best promoter that will be expressed exclusively in terminally differentiated epithelial cells; and, 2) To elicit SIV antigen expression from a terminally differentiated keratinocyte-specific promoter in rhesus macaques vaccinated by dermal, vaginal and rectal routes.