Molecular immunopathogenesis of cerebral toxoplasmosis

简介(申请人提供)：弓形体脑炎是一种 在免疫功能受损的患者中，如艾滋病患者，会出现危及生命的疾病。 TE的免疫发病机制尚不清楚。我们已经确认了三个 决定寄主对该病抗性的关键因素。 这些都是干扰素-伽马介导的免疫反应，这是 宿主和弓形虫株(抗原)。看起来遗传基因 弓形虫株(抗原)影响宿主的背景 干扰素-γ介导的免疫反应，从而有助于确定宿主 抵抗。因此，为了了解宿主的分子基础， 对于TE的耐药性，我建议定义干扰素-γ介导的机制 免疫反应是在大脑中进行的，以及 宿主和弓形虫的菌株(抗原)影响免疫反应。至 要实现这一长期的具体目标，我将在 这项提议。我最近的初步研究表明，受感染的无性恋者 缺乏T细胞的裸小鼠和SCID小鼠有高水平的干扰素-γ表达 在他们的大脑里。另一系列初步研究使用转移的 免疫T细胞证实这种干扰素-γ由非T细胞表达(S) 需要被转移的免疫T细胞来证明它们的保护作用 大脑中的活动，以防止血栓形成。因此，第一个具体目标是 脑内产生干扰素-γ的非T细胞(S)的鉴定及分析 T细胞在与非T细胞协同中的作用和功能(S) 预防血栓栓塞症。第二个具体目的是分析T的作用机制 被感染的宿主的细胞进入大脑。T细胞需要进入大脑才能 发挥它们的保护作用。我的初步研究表明一个重要的 干扰素-γ在调节T细胞向脑内转运中的作用 老鼠。因此，我建议分析干扰素-γ在调节 参与细胞转运的黏附分子在脑组织中的表达 血管和T细胞。在这个特定的目标下，我还建议分析 干扰素-γ和黏附分子在T细胞进入脑中的作用 第三个具体目的是解决宿主基因对保护性的影响 对TE的免疫反应。因为我的初步研究揭示了 携带Vbeta8的T细胞在BALB/c小鼠对TE的遗传抗性中的作用 分析这一T细胞群的保护作用机制 他们的抵抗。我还建议分析弓形虫抗原(S) 刺激携带Vbeta8的T细胞。

DESCRIPTION (Provided by the applicant): Toxoplasmic encephalitis (TE) is a life-threatening disease in immunocompromised patients such as those with AIDS. The immunopathogenesis of TE remains to be defined. We have identified three factors to be critical for determining the host resistance to this disease. These are IFN-gamma-mediated immune response, the genetic background of the host and the strain (antigens) of T. gondii. It appears that the genetic background of the hostand the strain (antigens) of T. gondii affect the IFN-gamma-mediated immune response, thereby contribute to determining the host resistance. Thus, for obtaining understanding of the molecular basis of host resistance to TE, I propose to define the mechanisms how IFN-gamma-mediated immune response is operated in the brain and how the genetic background of the host and the strain (antigens) of T. gondii affect the immune response. To accomplish this long-term specific aim, I will address three main questions in this proposal. My recent preliminary studies demonstrated that infected athymic nude and SCID mice, which lack T cells, had high levels of IFN-gamma expression in their brains. Another series of preliminary studies using a transfer of immune T cells demonstrated that such IFN-gamma expression by the non-T cell(s) is required for transferred immune T cells to demonstrate their protective activity in the brain to prevent TE. Thus, the first specific aim is to identify the non-T cell(s) which produces IFN-gamma in the brain and to analyze the role and function of T cells in their collaboration with the non-T cell(s) for prevention of TE. The second specific aim is to analyze the mechanism of T cell entry into the brain in infected host. T cells need to enter the brain to exert their protective activity. My preliminary studies suggested an important role for IFN-gamma, in regulating T cell trafficking into the brain of infected mice. Thus, I propose to analyze the role for IFN-gamma, in regulation of expression of adhesion molecules involved in cell trafficking on cerebral vessels and T cells. Under this specific aim, I also propose to analyze the role of IFN-gamma and adhesion molecules on the T cell entry into the brain. The third specific aim to address the effects of host genes on the protective immune response to TE. Since my preliminary studies revealed an importance of Vbeta8-bearing T cells in genetic resistance of BALB/c mice to TE, I propose to analyze the mechanism of the protective activity of this T cell population in their resistance. I also propose to analyze T. gondii antigen(s) which stimulate Vbeta8-bearing T cells.