TOXOPLASMA GONDII--ROLE OF IMMUNE CYTOKINES

细胞免疫对弓形虫的重要性是显而易见的。 感激不尽。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方面很重要。 我们实验室和其他实验室的观察表明，细胞因子产生 通过Th1型T细胞，特别是干扰素-γ、白介素2和白介素2- 12、能够加强保护。相反，这些免疫细胞因子 与Th2反应有关，特别是IL-4、IL-6，特别是 IL-10影响血管内皮细胞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(Th1)和痛苦之间的平衡 (Th2)反应可被特定的细胞因子拮抗剂操纵。 因此，这项提案的总体具体目标是确定 Th2类细胞因子在肿瘤发生发展中的作用 急、慢性实验过程中的免疫病理变化 弓形虫病。这些细胞因子的特定抑制剂将用于 改变自然感染的过程。第一个具体目标是 体外测定这些Th2细胞因子的作用机制 下调宿主的反应。重点将放在 IL-10、IL-6和IL-4在这一反应中的相对贡献。这个 脾、淋巴结和肠内上皮(IEL)细胞 将对这些细胞因子的产生进行鉴定和表征。 我们将确定Th2应答是否可以通过途径、剂量 或感染时处于寄生虫期。它们通过的机制 弓形虫诱导的细胞因子下调宿主应答细胞， 包括弓形虫作为超抗原的能力，将是 已评估。第二个具体目标将是在体内评估 Th2细胞因子诱导小鼠免疫病理改变的能力 受感染宿主的重要器官。炎性细胞-将是 半定量检测细胞因子的表型和数量 数量化方法。将确定是自然抵抗力还是 对感染的易感性部分归因于Th2细胞的差异 细胞因子图谱。不同寄生虫诱导的Th2细胞因子谱 将对菌株进行评估。最终的具体目标将是确定 用半定量方法测定细胞因子mRNA的含量。会的 确定对感染的天然抵抗力或易感性是否 部分原因是Th2细胞因子谱的差异。Th2细胞因子 将对不同寄生虫菌株诱导的图谱进行评估。决赛 具体目标将是确定Th2细胞因子的中和是否， 尤其是IL-10、IL-6和IL-4单独或联合抗- 弓形虫药物将提供一种相加或协同作用 弓形虫病小鼠模型的治疗。

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.