Vaccine-elicited genital and neuronal T cell responses

描述（由申请人提供）：2型单纯疱疹病毒（HSV-2）现在感染大约五分之一的美国人的生殖道。 针对HSV-2感染的保护非常依赖于强有力的抗原特异性T细胞应答的发展。 考虑到HSV-2在感染后很快扩散到感觉神经节的能力，如果疫苗要预防或大大减少感觉神经节中潜伏病毒感染的建立，则疫苗引发的T细胞将需要在初始感染后非常迅速地被激活、表达效应子功能并存在于适当的感染部位。因此，用有效的HSV疫苗免疫应该导致效应记忆T细胞部署到生殖器上皮，也许也到感觉神经节。在拟议的研究中，我们将重点关注HSV疫苗诱导的保护性T细胞免疫。具体来说，我们将研究部署HSV特异性记忆T细胞的生殖器上皮和感觉神经节的要求。 在目标1中，我们将使用ELISPOT分析来检测免疫后感觉神经节中的HSV特异性记忆T细胞，并测试感觉神经节中HSV特异性T细胞记忆的需求，以保护该组织免受HSV-2感染。目前正在开发的大多数HSV疫苗预计会引起体液免疫应答，并且主要是CD 4 + T细胞。在目标2中，我们将特异性地耗尽HSV免疫小鼠的T细胞亚群，以确定CD 4 + T细胞是否足以提供参与保护阴道上皮和感觉神经节的快速T细胞介导的组分。使用克隆型特异性单克隆抗体来检测体内抗原特异性T细胞，我们将在目标3中测试以当前HSV疫苗临床试验中使用的疫苗接种策略为模型的疫苗接种策略是否会导致记忆细胞部署到生殖器上皮和感觉神经节。我们还将测试是否可以通过1）在生殖道附近的粘膜或皮肤部位进行免疫接种和2）增加疫苗引发的T细胞应答的幅度来改善记忆T细胞在这些组织中的部署。在目的4中，我们将使用常规空斑测定和定量PCR测定来检测生殖器上皮和感觉神经节中的病毒，以测试与系统递送相同疫苗产生的保护相比，将HSV疫苗靶向生殖道是否导致T细胞介导的生殖器上皮和感觉神经节的更大保护。

DESCRIPTION (provided by applicant): Herpes simplex virus type 2 (HSV-2) now infects the genital tracts of approximately one in five Americans. Protection against HSV-2 infection is very dependent on the development of vigorous antigen-specific T cell responses. Given the ability of HSV-2 to spread to the sensory ganglia soon after infection, vaccine-elicited T cells will need to be activated, express effector function, and be present at the appropriate sites of infection very rapidly after initial infection if vaccines are to prevent or greatly reduce the establishment of latent virus infection in the sensory ganglia. Therefore, immunization with an effective HSV vaccine should result in the deployment of effector memory T cells to the genital epithelium and perhaps to the sensory ganglia as well. In the proposed studies we will focus on the induction of protective T cell immunity by HSV vaccines. Specifically we will examine the requirements for deployment of HSV-specific memory T cells to the genital epithelium and sensory ganglia. In Aim 1 we will use ELISPOT analysis to detect HSV-specific memory T cells in the sensory ganglia following immunization and test the requirement for HSV-specific T cell memory in the sensory ganglia to protect this tissue against HSV-2 infection. Most HSV vaccines currently being developed are expected to elicit humoral immune responses and predominantly CD4+ T cells. In Aim 2 we will specifically deplete T cell subsets from HSV-immune mice to determine if CD4+ T cells are sufficient to provide the rapid T cell mediated component involved in protection of the vagina epithelium and sensory ganglia. Using a clonotype-specific monoclonal antibody to detect antigen-specific T cells in vivo, we will test in Aim 3 if vaccination strategies modeled after those used in current HSV vaccine clinical trials will result in deployment of memory cells to the genital epithelium and sensory ganglia. We will also test if deployment of memory T cells to these tissues can be improved by 1) immunization at mucosal or cutaneous sites near the genital tract and 2) increasing the magnitude of the vaccine elicited T cell response. In Aim 4 we will use conventional plaque assays and quantitative PCR assays to detect virus in the genital epithelia and sensory ganglia to test if targeting an HSV vaccine to the genital tract results in greater T cell mediated protection of the genital epithelia and sensory ganglia compared to the protection resulting from systemic delivery of the same vaccine.