INTERFERON GAMMA EFFECTS ON OLIGODENDROCYTES

干扰素γ对少突胶质细胞的影响

• 批准号: 6126275
• 负责人: Brian J Popko
• 金额: $ 22.13万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6126275
• 关键词: cytokine receptors; experimental allergic encephalomyelitis; genetically modified animals; helper T lymphocyte; interferon gamma; laboratory mouse; macrophage; microglia; myelin; myelin basic proteins; neuropharmacology; nitric oxide; oligodendroglia; proteolipids; tumor necrosis factor alpha

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.

尽管多发性硬化症（MS）的病因尚未明确 已确定，人们普遍认为免疫机制 涉及。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。 EAE 可诱发 通过中枢神经系统组织、髓磷脂或髓磷脂进行免疫接种的动物 成分。 在 MS 和 EAE 中，中枢神经系统浸润增加 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， 中枢神经系统。我们假设 IFN-gamma 是一个关键的调节因子 MS 和 EAE 中的脱髓鞘。该提案的目标是审查 IFN-γ对髓鞘形成过程和髓磷脂的影响 使用几种体内模型的鞘。 IFN-γ对细胞的影响 转基因小鼠的髓鞘形成过程将得到详细表征 其中 IFN-γ 的表达已靶向 CNS。 这些转基因（MBP/IFN-γ）动物的髓鞘严重不足， 强烈表明 IFN-γ 的存在对 髓鞘形成过程。 我们还将检查 IFN-的影响 使用微渗泵对已经有髓鞘的中枢神经系统进行伽玛 将这种细胞因子输送到成人中枢神经系统。 建议使用 IFN-γ 通过以下方式对脱髓鞘疾病产生间接影响 巨噬细胞/小胶质细胞的激活，进而产生 被认为的物质（肿瘤坏死因子和一氧化氮） 对少突胶质细胞具有细胞毒性。我们推测 IFN-γ 可能 对少突胶质细胞也有直接影响。努力开始 为了了解中枢神经系统中 IFN-γ 的细胞作用位点，我们 将检查这种细胞因子对转基因小鼠的影响，其中 巨噬细胞，可能还有小胶质细胞，对 IFN-γ 没有反应。 此外，还将在 SJL 小鼠中检查 EAE 的各种参数 其中 IFN-γ 基因已被基因灭活。一起， 我们相信这些研究将极大地促进我们 了解 IFN-γ 的潜在影响和作用位点 免疫介导的中枢神经系统脱髓鞘疾病。这样的 信息对于合理设计治疗方案至关重要 针对这些疾病的策略。