INTERFERON GAMMA EFFECTS ON OLIGODENDROCYTES

描述(摘自申请者的摘要)：人类脱髓鞘 多发性硬化症(MS)及其动物模型实验性自身免疫 脑脊髓炎(EAE)，有血脑屏障的破坏和 免疫细胞渗入中枢神经系统。浸润性T淋巴细胞和 巨噬细胞被认为是疾病过程的关键媒介。 大量的间接证据和实验证据表明， 多效性细胞因子干扰素-γ(干扰素-γ)，它是唯一的 由T细胞和自然杀伤细胞表达，是一种有害的成分 这些疾病中的免疫反应。我们已经证明，当异位 在转基因动物的中枢神经系统中表达的干扰素-γ促进了许多 发生在免疫介导性脱髓鞘疾病中的病理变化。这个 干扰素-γ对中枢神经系统髓鞘的有害作用可能是介导的，至少在 部分，通过直接作用于髓鞘细胞。为了支持这一点 假设我们已经证明了这种细胞因子在 体外培养的少突胶质细胞，包括其凋亡性细胞死亡。我们已经展示了 也产生了体内数据，表明一个有害的影响 干扰素-γ涉及内质网(ER)超载。 主要组织相容性复合体诱导的少突胶质细胞 (MHC)I类重链基因表达。在当前的应用程序中，我们计划 在这些研究的基础上，进一步探索这种细胞因子所起的作用 在免疫介导的脱髓鞘疾病中。我们将建立第二代 转基因动物，使用四环素诱导系统，将使我们 控制干扰素-γ进入中枢神经系统。利用这些动物，我们将检查 干扰素-γ的存在对髓鞘再生过程的影响 脱髓鞘的铜试剂模型。我们还将审查成员是否 新发现的被称为细胞因子信号抑制因子的蛋白质家族 (SOCs)能够保护少突胶质细胞免受 干扰素-γ。此外，我们将从生物化学和遗传学角度研究 干扰素-γ对少突胶质细胞的主要作用可能是 通过内质网应激的诱导而介导。总而言之，这些研究将 大大加深了我们对细胞和分子效应的理解 免疫细胞渗入中枢神经系统。这些信息对于 治疗策略的基本原理设计。

DESCRIPTION (From the Applicant's Abstract): In the human demyelinating disorder multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE), there is a breakdown of the blood-brain barrier and an infiltration of immune cells into the CNS. Infiltrating T lymphocytes and macrophages are believed to be key mediators of the disease process. Considerable circumstantial and experimental evidence has suggested that the pleiotropic cytokine interferon gamma (IFN-gamma), which is exclusively expressed by T cells and natural killer cells, is a deleterious component of the immune response in these disorders. We have shown that when ectopically expressed in the CNS of transgenic animals IFN-y promotes many of the pathological changes that occur in immune-mediated demyelinating disorders. The harmful actions of IFN-gamma on CNS myelin are likely mediated, at least in part, through direct effects on the myelinating cells. In support of this hypothesis we have shown that this cytokine elicits a number of effects on oligodendrocytes in vitro, including their apoptotic cell death. We have shown also generated in vivo data that suggests that one detrimental effect of IFN-gamma involves overloading the endoplasmic reticulum (ER) of oligodendrocytes through the induction of major histocompatibility complex (MHC) class I heavy chain gene expression. In the current application we plan to build on these studies to further explore the role that this cytokine plays in immune-mediated demyelinating disorders. We will establish second generation transgenic animals, using the tetracycline-induction system that will allow us to control IFN-gamma delivery into the CNS. Using these animals we will examine the effect of the presence of IFN-gamma on the remyelination process exploiting the cuprizone model of demyelination. We will also examine whether members of a newly discovered family of proteins, termed suppressors of cytokine signaling (SOCS), are able to protect oligodendrocytes from the deleterious actions of IFN-gamma. Moreover, we will examine biochemically and genetically the possibility that the primary effect of IFN-gamma on oligodendrocytes is mediated through the induction of ER stress. Together, these studies will significantly further our understanding of the cellular and molecular effects of immune cell infiltration into the CNS. Such information is critical to the rationale design of therapeutic strategies.