IFN GAMMA--ROLES IN DEMYELINATION AND AUTOIMMUNITY

γ 干扰素——在脱髓鞘和自身免疫中的作用

• 批准号: 2858223
• 负责人: CLAIRE Frances EVANS
• 金额: $ 11.82万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2858223
• 关键词: autoimmunity; enzyme activity; gene induction /repression; genetically modified animals; histocompatibility antigens; immunogenetics; interferon gamma; interleukin 1; laboratory mouse; multiple sclerosis; myelinopathy; nitric oxide; nitric oxide synthase; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION: Interferon-gamma (IFN-gamma) is a cytokine produced in response to some microbial infections, that has widespread effects throughout the body. It influences the development and differentiation of cells involved in immune responses and regulates the expression of activation, adhesion, and major histocompatibility (MHC) molecules on many cell types. Several studies have implicated IFN-gamma in the pathology of central nervous system (CNS) demyelinating diseases, such as multiple sclerosis (MS). To address the effects of persistent expression of IFN-gamma in selected regions of the CNS, Dr Evans generated transgenic mice that express murine IFN-gamma in oligodendrocytes in the CNS. Expression of the transgene began after eight weeks of age, and resulted in primary axonal demyelination throughout the CNS accompanied by weight loss, weakness, and premature death. Dr Evans' results demonstrated that IFN-gamma can induce CNS demyelination leading to clinical disease. This proposal addresses the mechanisms by which IFN-gamma induces CNS demyelination, and the effects of constitutive CNS expression of IFN-gamma on models of CNS autoimmune disease. The first Specific Aim tests the hypothesis that IFN-gamma-induced demyelination occurs indirectly by influencing the expression of other cytokine and/or MHC gene expression in the CNS. The second Aim tests the hypothesis that expression of IFN-gamma in the CNS induces the synthesis of nitric oxide, which is toxic to myelin. The third Aim addresses the hypothesis that the expression of IFN-gamma in the CNS leads to increased susceptibility to autoimmune disease in the CNS. The effect of IFN-gamma on the course of two experimentally-induced autoimmune diseases will be evaluated. The long-term objectives of this application are to define the roles of IFN-gamma in CNS demyelination and autoimmunity. The ultimate goals are an understanding of the mechanism of demyelination in MS, and the design of therapies to treat and prevent this disease.

描述： 干扰素-γ (IFN-gamma) 是一种细胞因子，产生于 对某些微生物感染的反应，具有广泛的影响 遍布全身。 它影响着个体的发育和分化 参与免疫反应的细胞并调节 许多细胞上的激活、粘附和主要组织相容性 (MHC) 分子 细胞类型。 多项研究表明 IFN-γ 与以下疾病的病理学有关： 中枢神经系统（CNS）脱髓鞘疾病，例如多发性 硬化症（MS）。 为了解决持续表达的影响 埃文斯博士在中枢神经系统的选定区域中培育出 IFN-gamma 转基因小鼠 在中枢神经系统少突胶质细胞中表达鼠干扰素-γ。 表达 转基因在八周龄后开始，并产生初级轴突 整个中枢神经系统脱髓鞘，伴有体重减轻、虚弱和 过早死亡。 埃文斯博士的结果表明，IFN-γ可以诱导 中枢神经系统脱髓鞘导致临床疾病。 该提案解决了 IFN-γ诱导中枢神经系统脱髓鞘的机制，以及 CNS自身免疫模型中IFN-γ的组成性CNS表达 疾病。 第一个具体目标检验了 IFN-gamma 诱导的假设 脱髓鞘通过影响其他细胞的表达而间接发生 CNS 中的细胞因子和/或 MHC 基因表达。 第二个目标测试 假设中枢神经系统中 IFN-γ 的表达诱导合成 一氧化氮，对髓磷脂有毒。 第三个目标提出了这样的假设：IFN-γ 的表达 中枢神经系统导致中枢神经系统对自身免疫性疾病的易感性增加。 IFN-γ对两种实验诱导病程的影响 将评估自身免疫性疾病。 本次活动的长期目标 应用是确定 IFN-γ 在中枢神经系统脱髓鞘中的作用和 自身免疫。 最终目标是了解其机制 多发性硬化症的脱髓鞘，以及治疗和预防这种情况的疗法设计 疾病。