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)的病因尚未得到 人们普遍认为，免疫机制是 牵涉其中。实验性自身免疫性脑脊髓炎(EAE)是 用于研究MS EAE的主要动物模型可在 用中枢神经系统组织、髓鞘或髓鞘免疫的动物 组件。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(干扰素-γ)，通常不存在于体内， 中枢神经系统。我们假设干扰素-γ是一种关键的 MS-和EAE中的脱髓鞘。这项提案的目标是审查 干扰素-γ对髓鞘形成过程和髓鞘的影响 鞘使用了几个活体模型。干扰素-γ对小鼠血管内皮细胞生长的影响 转基因小鼠的髓鞘形成过程将得到详细描述。 其中干扰素-γ的表达已靶向中枢神经系统。 这些转基因(MBP/干扰素-伽马)动物的髓鞘严重不足， 强烈表明干扰素-γ的存在对人体有害 髓鞘形成过程。我们还将研究干扰素的作用- 使用微渗泵对已经很好的髓鞘中枢神经系统进行伽玛治疗 将这种细胞因子传递到成年中枢神经系统。干扰素-伽马已经被建议 通过对脱髓鞘障碍有间接影响 激活巨噬细胞/小胶质细胞，进而产生 人们认为的物质(肿瘤坏死因子和一氧化氮) 对少突胶质细胞有细胞毒性。我们推测干扰素-γ可能 对少突胶质细胞也有直接影响。为了开始 为了了解干扰素-γ在中枢神经系统中的作用部位，我们 将在转基因小鼠中检测这种细胞因子的作用 巨噬细胞，可能还有小胶质细胞，对干扰素-γ没有反应。 此外，还将在SJL小鼠身上检测EAE的各种参数 其中干扰素-伽马基因已被基因灭活。一起， 我们相信，这些研究将大大促进我们的 对干扰素-γ的潜在作用和作用部位的认识 在免疫介导的中枢神经系统脱髓鞘疾病中。是这样的 信息是合理设计治疗方案的关键 针对这些障碍的策略。