Molecular immunopathogenesis of cerebral toxoplasmosis

描述（由申请人提供）：弓形虫脑炎（TE）是一种 危及生命的疾病，免疫功能低下的患者，如艾滋病患者。 TE的免疫发病机制仍有待确定。我们已经确定了三个 这些因素对于确定宿主对这种疾病的抗性至关重要。 这些是IFN-γ介导的免疫反应， 宿主和T.刚地。似乎基因 宿主背景和T.弓形虫感染 IFN-γ介导的免疫应答，从而有助于确定宿主 阻力因此，为了了解宿主的分子基础， 抗TE，我建议定义IFN-γ介导的机制， 免疫反应是在大脑中运作的， 宿主和T.弓形虫影响免疫反应。到 为了实现这一长期的具体目标，我将讨论三个主要问题， 这个提议。我最近的初步研究表明， 缺乏T细胞的裸鼠和SCID小鼠有高水平的IFN-γ表达， 在他们的大脑中。另一系列的初步研究使用了转移 免疫T细胞证实了这种非T细胞的IFN-γ表达 是转移的免疫T细胞所必需的，以证明其保护性 大脑中的活动，以防止TE。因此，第一个具体目标是 鉴定脑中产生IFN-γ的非T细胞，并分析 T细胞在与非T细胞协作中的作用和功能 预防TE。第二个具体目标是分析T 细胞进入受感染宿主的大脑T细胞需要进入大脑， 发挥他们的保护作用。我的初步研究表明 IFN-γ在调节T细胞进入感染者大脑中的作用 小鼠因此，我建议分析IFN-γ的作用，在调节 参与细胞运输的粘附分子在脑组织中的表达 血管和T细胞。在这一具体目标下，我还建议分析 IFN-γ和粘附分子在T细胞进入脑中的作用。 第三个具体目标是解决宿主基因对保护作用的影响 对TE的免疫反应。因为我的初步研究显示 携带V β 8的T细胞在BALB/c小鼠对TE的遗传抗性中的作用，我建议 分析这种T细胞群体的保护活性的机制， 他们的抵抗。我还建议分析T.弓形虫抗原， 刺激携带V β 8 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.