C-Rel in resistance to toxoplasma gondii

描述（由申请人提供）：本提案的总体目标是 了解c-Rel的作用，它是转录的NF-κ B家族的成员 调节对机会性病原体的免疫应答的因素， 弓形虫尽管NF-κ B家族成员与 调节先天性和适应性免疫所需的免疫功能， 关于它们在感染过程中的实际作用知之甚少。患者 原发性和获得性免疫缺陷对T.弓形虫 感染对这种病原体的抵抗取决于IL-12的能力， 刺激IFN-γ的产生c-Rel与许多事件有关 导致IFN-γ的产生。例如，c-Rel与 IL-12的产生，并参与细胞内信号传导 许多免疫分子如CD 28和TNF α的途径， NK细胞和T细胞产生IFN-γ。此外，c-Rel结合位点 已在IL-2基因和c-Rel -/- T细胞的启动子中鉴定出 缺乏IL-2的产生并表现出增殖缺陷。我们 研究表明c-Rel -/-小鼠对T. 与寄生虫数量增加和IFN-γ减少相关的弓形虫 生产初步的研究表明，有一个早期的缺陷，在 在感染部位产生IL-12。我们还在体内显示， 在体外，c-Rel对于从巨噬细胞产生IL-12是必需，但 而不是树突细胞。根据这些初步研究，我们建议执行 研究c-Rel在IL-12产生中的作用的实验， IFN-γ。这些研究将使我们进一步了解 导致c-Rel -/-小鼠对弓形虫的易感性增加。在 此外，IL-12和IFN-γ介导对许多细胞内病毒抗性， 细菌和寄生虫感染。我们的研究将使我们能够进一步 了解负责生产IFN-γ的机制， 细胞因子是抵抗许多机会性的 感染艾滋病患者。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to understand the role of c-Rel, a member of the NF-kappaB family of transcription factors in regulation of the immune response to the opportunistic pathogen, Toxoplasma gondii. Athough the NF-kappaB family members are associated with the regulation of immune function required for innate and adaptive immunity, little is known about their actual role during infection. Patients with primary and acquired immune deficiencies are highly susceptible to T. gondii infection. Resistance to this pathogen is dependent upon the ability of IL-12 to stimulate the production of IFN-gamma. c-Rel is associated with many events leading to the production of IFN-gamma. For example, c-Rel is associated with the production of IL-12 and is involved in the intracellular signaling pathways of many immune molecules such as CD28 and TNF alpha that enhance IFN-gamma production by NK cells and T cells. Furthermore, c-Rel binding sites have been identified in the promoter of the IL-2 gene and c-Rel -/- T cells are deficient in the production of IL-2 and exhibit proliferation defects. Our studies have shown that c-Rel -/- mice have an increased susceptibility to T. gondii associated with increased numbers of parasites and reduced IFN-gamma production. Preliminary studies suggest that there is an early defect in the production of IL-12 at the site of infection. We have also shown in vivo and in vitro, that c-Rel is essential for IL-12 production from macrophages but not dendritic cells. Based on these preliminary studies, we propose to perform experiments which address the role of c-Rel in the production of IL-12 and IFN-gamma. These studies will allow us to further understand the mechanisms responsible for the increased susceptibility of c-Rel -/- mice to T gondii. In addition, IL-12 and IFN-gamma mediate resistance to many intracellular viral, bacterial and parasitic infections. Our studies will allow us to further understand the mechanisms responsible for the production of IFN-gamma, a cytokine that is critical for resistance to many of the opportunistic infections which affect patients with AIDS.