IFN GAMMA--ROLES IN DEMYELINATION AND AUTOIMMUNITY

描述：干扰素是一种细胞因子，产生于 对一些微生物感染的反应，这具有广泛的影响 遍及全身。它影响着人类的发展和分化 参与免疫反应的细胞并调节其表达 活化、黏附和主要组织相容性(MHC)分子在许多 单元类型。已有多项研究表明干扰素-γ与慢性粒细胞白血病的病理机制有关。 中枢神经系统(CNS)脱髓鞘疾病，如多发性 硬化症(MS)。要解决持续表达的影响 在选定的中枢神经系统区域，埃文斯博士产生了转基因小鼠 在中枢神经系统的少突胶质细胞中表达小鼠干扰素-γ。的表达 转基因在8周后开始，并导致了初级轴突。 整个中枢神经系统的脱髓鞘伴随着体重减轻、虚弱和 过早死亡。埃文斯博士的结果表明，干扰素-γ可以诱导 中枢神经系统脱髓鞘导致临床疾病。这项建议解决了 干扰素-γ诱导中枢神经系统脱髓鞘的机制及其作用 干扰素-γ在中枢神经系统自身免疫模型中的组成性表达 疾病。第一个特定的目标是检验干扰素-γ诱导的假设 脱髓鞘是通过影响其他基因的表达间接发生的 细胞因子和/或MHC基因在中枢神经系统的表达。第二个目标是测试 假设干扰素-γ在中枢神经系统中的表达诱导合成 一氧化氮，对髓鞘有毒性。 第三个目标解决了这样的假设，即干扰素-γ在体内的表达 中枢神经系统导致中枢神经系统自身免疫性疾病的易感性增加。 干扰素-γ对小鼠实验性脑出血过程的影响 将对自身免疫性疾病进行评估。这个项目的长期目标是 应用是确定干扰素-γ在中枢神经系统脱髓鞘和 自身免疫力。我们的最终目标是理解 多发性硬化症的脱髓鞘及治疗和预防方法的设计 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.