Migration Inhibitory Factor in the Progression of EAE

EAE 进展中的迁移抑制因素

• 批准号: 7030078
• 负责人: CAROLINE C WHITACRE
• 金额: $ 37.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-15 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030078
• 关键词: bone marrow; cell population study; cytokine; experimental allergic encephalomyelitis; glucocorticoids; histopathology; hormone regulation /control mechanism; laboratory mouse; lymphocyte; migration inhibition factor; multiple sclerosis; myelin glycoprotein; pathologic process; tissue mosaicism

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CMS) which can present as a remitting/relapsing, primary progressive, secondary progressive or progressive relapsing form. Experimental autoimmune encephalomyelitis (EAE), a frequently studied animal model for MS, is inducible in the commonly used C57BL/6 mouse, which develops a progressive course of EAE when immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. A major focus of research in EAE and MS has been what causes progression of disease and is there a signal which can be used to predict a relapse or worsening of disease. Migration inhibitory factor (MIF) has recently been re-discovered as an inducer of pro- inflammatory cytokines and an antagonist of glucocorticoid hormones. We examined the role of MIF in acute and chronic EAE using MIF knock-out mice. We found that MIF-/- mice showed signs of acute EAE identical to wild type (WT) controls but did not exhibit progression of disease. MIF-/- mice showed elevated levels of corticosterone and decreased levels of pro-inflammatory cytokines. In light of these findings and reports by others that colitis is suppressed in MIF-deficient animals, we pose the hypothesis that MIF derived from myeloid cells is necessary for progression of EAE. We will first determine the cellular source of MIF which is necessary for progressive EAE using a series of bone marrow chimeras in which various cell types are rendered MIF deficient. Second, we will gain a better understanding of the role played by MIF in disease progression by examining priming, CNS histopathologic changes, glucocorticoid hormone release, and cytokine changes. At the completion of these studies, we will have determined the source of the biologically relevant MIF and will have a clearer picture of the role played by MIF in causing progression of EAE. During the course of this project, we will repeatedly evaluate the possibility that MIF could serve as a target for new therapies in MS. RELEVANCE TO PUBLIC HEALTH: Multiple sclerosis is a disease affecting over 300,000 persons in the US which affects their ability to work and lead a productive life. It begins early in life and often progresses slowly leading to severe disability. This project studies a key factor involved in disease progression and will identify specific points in disease when therapeutic intervention is likely to be successful.

描述（由申请人提供）：多发性硬化症（MS）是中枢神经系统（CMS）的脱髓鞘疾病，其可以表现为缓解/复发、原发进行性、继发进行性或进行性复发形式。实验性自身免疫性脑脊髓炎 (EAE) 是一种经常研究的多发性硬化症动物模型，可在常用的 C57BL/6 小鼠中诱导，当用髓磷脂少突胶质细胞糖蛋白 (MOG) 肽 35-55 免疫时，该小鼠会出现进行性 EAE 病程。 EAE 和 MS 研究的一个主要焦点是导致疾病进展的原因以及是否存在可用于预测疾病复发或恶化的信号。迁移抑制因子（MIF）最近被重新发现为促炎细胞因子的诱导剂和糖皮质激素的拮抗剂。我们使用 MIF 敲除小鼠研究了 MIF 在急性和慢性 EAE 中的作用。我们发现 MIF-/- 小鼠表现出与野生型 (WT) 对照相同的急性 EAE 迹象，但没有表现出疾病进展。 MIF-/-小鼠表现出皮质酮水平升高和促炎细胞因子水平降低。鉴于这些发现和其他人关于 MIF 缺陷动物中结肠炎受到抑制的报告，我们提出假设，源自骨髓细胞的 MIF 对于 EAE 的进展是必需的。我们将首先使用一系列骨髓嵌合体来确定进行性EAE所必需的MIF的细胞来源，其中各种细胞类型都缺乏MIF。其次，我们将通过检查启动、中枢神经系统组织病理学变化、糖皮质激素释放和细胞因子变化，更好地了解 MIF 在疾病进展中发挥的作用。这些研究完成后，我们将确定生物学相关的 MIF 的来源，并对 MIF 在导致 EAE 进展中所起的作用有更清晰的了解。在这个项目过程中，我们将反复评估 MIF 作为 MS 新疗法靶点的可能性。与公众健康的相关性：多发性硬化症是一种影响美国超过 300,000 人的疾病，影响他们的工作和过上富有成效的生活的能力。它始于生命早期，通常进展缓慢，导致严重残疾。该项目研究涉及疾病进展的关键因素，并将确定治疗干预可能成功时疾病的特定点。