TOXOPLASMA GONDII--ROLE OF IMMUNE CYTOKINES

细胞免疫对T.弓形虫很好 赞赏.最近的研究表明，免疫细胞因子是 在调节宿主对寄生虫感染的反应中很重要。 我们实验室和其他实验室的观察表明， 通过假定的Th 1型T细胞，特别是IFN-γ、IL-2和IL-10， 12、加强保护。相反，那些免疫细胞因子 与Th 2应答相关的，特别是IL-4、IL-6， IL-10，影响免疫病理改变的发展， 感染宿主导致发病率和死亡率增加。我们 假设保护性（Th 1）和痛苦性之间的平衡 (Th2)可以通过特异性细胞因子拮抗剂操纵应答。 因此，本提案的总体具体目标是确定 这些Th 2细胞因子的作用，影响的发展， 急性和慢性实验性肝损伤的免疫病理变化 弓形虫病这些细胞因子的特异性抑制剂将用于 改变自然感染的过程。第一个具体目标是 在体外确定这些Th 2细胞因子 下调宿主的反应重点将放在 IL-10、IL-6和IL-4在该应答中的相对贡献。的 脾、淋巴结和肠内上皮（IEL）细胞负责 将鉴定和表征这些细胞因子的产生。 我们将确定Th 2应答是否可以通过途径、剂量 或寄生虫阶段。这些机制 T.弓形虫诱导的细胞因子下调宿主应答细胞， 包括T.作为一种超抗原， 评估。第二个具体目标将是在体内评价 Th 2细胞因子诱导免疫病理变化的能力， 感染宿主的重要器官。炎症细胞-将 表型和细胞因子mRNA的数量通过半定量 定量方法将确定是否存在自然抵抗力或 对感染易感性部分是由于Th 2 细胞因子谱。不同寄生虫诱导的Th 2细胞因子谱 将对菌株进行评估。最终的具体目标是确定是否 通过半定量方法测量细胞因子mRNA的量。它将 确定是否存在对感染的天然抵抗力或易感性， 部分原因是Th 2细胞因子谱的差异。th 2细胞因子 将评估由不同寄生虫菌株诱导的分布。最终 具体目的是确定是否中和Th 2细胞因子， 特别是IL-10、IL-6和IL-4单独或与抗- 弓形虫药物将提供累加或协同作用， 治疗鼠模型中的弓形虫病。

The importance of cell mediated immunity to T. gondii is well appreciated. Recent studies have indicated that immune cytokines are important in modulating the host response to parasite infection. Observations in our laboratories and others show that cytokines produced by the presumptive Th1 type T cell, in particular IFN-gamma, IL-2 and IL- 12, are able to enhance protection. Conversely, those immune cytokines associated with the Th2 response, in particular IL-4, IL-6 and especially IL-10, influence the development of immunopathogenic alterations in the infected host resulting in increased morbidity and mortality. We hypothesize that the balance between protective (Th1) and afflictive (Th2) response can be manipulated by specific cytokine antagonists. Accordingly, the overall specific aim of this proposal is to determine the role of those Th2 cytokines that influence the development of immunopathologic changes during acute and chronic experimental toxoplasmosis. Specific inhibitors of these cytokines will be used to alter the course of natural infection. The first specific aim is to determine in vitro the mechanisms by which these Th2 cytokines downregulate the host response. Emphasis will be directed toward the relative contribution of IL-10, IL-6 and IL-4 in this response. The spleen, lymph node and intraintestinal epithelial (IEL) cells responsible for production of these cytokines will be identified and characterized. We will determine whether the Th2 response can be altered by route, dose or parasite stage at the time of infection. The mechanism by which these T. gondii induced cytokines downregulate the host responder cells, including the ability of T. gondii to act as a superantigen, will be evaluated. The second specific aim will be to evaluate in vivo the ability of the Th2 cytokines to induce immunopathogenic changes in the vital organs of the infected host. The inflammatory cells - will be phenotyped and the quantity of cytokine mRNA measured by semi- quantitative methods. It will be determined if natural resistance or susceptibility to infection are due in part to differences in Th2 cytokine profiles. The Th2 cytokine profile induced by different parasite strains will be assessed. The final specific aim will be to determine if quantity of cytokine mRNA measured by semi-quantitative methods. It will be determined if natural resistance or susceptibility to infection are due in part to differences in Th2 cytokine profiles. The Th2 cytokine profile induced by different parasite strains will be assessed. The final specific aim will be to determine if neutralization of the Th2 cytokines, in particular IL-10, IL-6 and IL-4 alone or in combination with anti- toxoplasma drugs will provide an additive or synergistic effect for treatment of toxoplasmosis in murine model.