INTERFERON GAMMA EFFECTS ON OLIGODENDROCYTES

虽然多发性硬化症（MS）的病因尚未得到证实， 建立后，人们普遍认为免疫机制 涉案实验性自身免疫性脑脊髓炎（EAE）是 MS研究中使用的主要动物模型。 用CNS组织、髓磷脂或髓磷脂免疫动物 件. 在MS和EAE中， T淋巴细胞 这些浸润性T细胞分泌细胞因子 干扰素-γ（IFN-γ），通常不存在于， CNS。我们假设IFN-γ是一个关键的介导者， MS和EAE中的脱髓鞘。这项提案的目的是审查 IFN-γ对髓鞘形成过程和髓鞘的影响 鞘管使用几种体内模型。IFN-γ对细胞凋亡的影响 髓鞘形成过程将在转基因小鼠中详细表征 其中IFN-γ的表达靶向CNS。 这些转基因（MBP/IFN-γ）动物严重髓鞘化不足， 这强烈表明IFN-γ的存在不利于 髓鞘形成过程 我们还将研究干扰素的作用- 使用微渗透泵， 将这种细胞因子传递到成年人的中枢神经系统。 IFN-γ被认为是 通过药物对脱髓鞘疾病产生间接影响 激活巨噬细胞/小胶质细胞，这反过来又产生 肿瘤坏死因子和一氧化氮被认为是 对少突胶质细胞有细胞毒性我们推测IFN-γ可能 也对少突胶质细胞有直接影响。为了努力开始 为了了解IFN-γ在中枢神经系统中的细胞作用部位，我们 将研究这种细胞因子在转基因小鼠中的作用， 巨噬细胞和可能的小胶质细胞对IFN-γ无反应。 此外，将在SJL小鼠中检查EAE的各种参数， 其中IFN-γ基因已经被遗传灭活。在一起， 我们相信，这些研究将大大促进我们的 了解IFN-γ的潜在作用和作用部位 免疫介导的中枢神经系统脱髓鞘疾病。等 信息对于合理设计治疗方案至关重要， 这些疾病的治疗策略。

Although the etiology of multiple sclerosis (MS) has not been established, it is widely believed that immunological mechanisms are involved. Experimental autoimmune encephalomyelitis (EAE) is the primary animal model used in the study of MS. EAE can be induced in animals by immunization with either CNS tissue, myelin, or myelin components. In MS and EAE, there is an increased CNS infiltration of T-lymphocytes. These infiltrating T-cells secrete the cytokine interferon-gamma (IFN-gamma), which is not normally present within, the CNS. We hypothesize that IFN-gamma is a key mediator of demyelination in MS -and EAE. The goal of this proposal is to examine the effects of IFN-gamma on the myelination process and the myelin sheath using several in vivo models. The effects of IFN-gamma on the myelination process will be characterized in detail in transgenic mice in which the expression of IFN-gamma has been targeted to the CNS. These transgenic (MBP/IFN-gamma) animals are severely hypomyelinated, strongly suggesting that the presence of IFN-gamma is detrimental to the myelination process. We will also examine the effects of IFN- gamma on an already well-myelinated CNS using microosmotic pumps to deliver this cytokine to the adult CNS. IFN-gamma has been suggested to have an indirect effect in demyelinating disorders through the activation of macrophages/microglial cells, which in turn produce substances (tumor necrosis factor and nitric oxide) that are thought to be cytotoxic to oligodendrocytes. We speculate that IFN-gamma may also have a direct effect on oligodendrocytes. In an effort to begin to understand the cellular site of action of IFN-gamma in the CNS, we will examine the effects of this cytokine in transgenic mice in which macrophages, and presumably microglia, are unresponsive to IFN-gamma. Moreover, various parameters of EAE will be examined in SJL mice in which the IFN-gamma gene has been genetically inactivated. Together, we believe that these studies will significantly further our understanding of the potential effects and site of action of IFN-gamma in immune-mediated demyelinating disorders of the CNS. Such information is critical for the rational design of therapeutic strategies for these disorders.