IFN GAMMA--ROLES IN DEMYELINATION AND AUTOIMMUNITY

描述：干扰素-γ（IFN-γ）是一种细胞因子， 对某些微生物感染的反应，具有广泛的影响 在整个身体。 它影响着植物的发育和分化， 参与免疫反应的细胞，并调节 活化，粘附和主要组织相容性（MHC）分子在许多 细胞类型。 几项研究表明IFN-γ与肿瘤的病理学有关， 中枢神经系统（CNS）脱髓鞘疾病，如多发性 硬化症（MS）。 为了解决持续表达 埃文斯博士通过在中枢神经系统的特定区域产生IFN-γ， 在CNS的少突胶质细胞中表达鼠IFN-γ。 表达 转基因在八周龄后开始，并导致初级轴突 整个CNS的脱髓鞘伴随体重减轻、虚弱和 过早死亡 埃文斯博士的研究结果表明，干扰素-γ可以诱导 CNS脱髓鞘导致临床疾病。 该提案针对 IFN-γ诱导CNS脱髓鞘的机制，以及IFN-γ的作用。 IFN-γ在CNS自身免疫模型上的组成型CNS表达 疾病 第一个特异性目的测试了IFN-γ诱导 脱髓鞘通过影响其他神经元的表达而间接发生。 CNS中的细胞因子和/或MHC基因表达。 第二个目标是测试 假设IFN-γ在CNS中的表达诱导 一氧化氮对髓磷脂有毒 第三个目的是解决以下假设，即IFN-γ的表达与IFN-γ的表达相关。 中枢神经系统导致中枢神经系统中自身免疫疾病的易感性增加。 IFN-γ对两种实验性诱导的 将评估自身免疫性疾病。 这一长期目标 应用是定义IFN-γ在CNS脱髓鞘中的作用， 自身免疫 最终的目标是理解 MS脱髓鞘，以及治疗和预防这种脱髓鞘的疗法设计 疾病

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.