PATHOGENESIS AND PREVENTION OF EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS

实验性过敏性脑脊髓炎的发病机制及预防

• 批准号: 6484676
• 负责人: CHARLES A JANEWAY
• 金额: $ 24.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6484676
• 关键词: B lymphocyte; CD95 molecule; T cell receptor; T lymphocyte; antibody formation; antigen presenting cell; cellular pathology; disease /disorder model; disease /disorder prevention /control; experimental allergic encephalomyelitis; gene mutation; gene rearrangement; gene targeting; genetically modified animals; immunoregulation; laboratory mouse; leukocyte activation /transformation; multiple sclerosis; myelin basic proteins; passive immunization; pathologic process; polymerase chain reaction; selectins; tissue /cell culture

This grant will examine the regulation of the murine autoimmune disease experimental allergic encepholmyelitis (EAE), a mouse model for the human disease multiple sclerosis, in four different ways. First, we seek to understand why mice without B cells fail to fully resolve their disease. We will approach this by breeding B-less mice to mice with a heavy chain transgene that cannot be secreted, to determine if antibody production is necessary for resolution of disease, or if it is the presence of antigen- specific B cells that is critical. Second, we seek an answer to the question of why mice bearing a transgenic T cell receptor specific for the N-terminal acetylated residues of myelin basic protein (AC1-16) become spontaneously ill in the absence of endogenous gene arrangement. We will ask two questions about such mice: First, we will determine the nature of the missing cell or cells through the use of gene knock-out technology. When we know what type of cell(s) it is, we will transfer such cells into these mice and look for protection from disease, and we will attempt to clone such cells. We will also test the hypothesis that auto-aggressive T cells can be switched to protective T cells by feeding myelin basic protein. Third, we will explore the mechanism of spontaneous disease in heterozygous progeny of mice bearing the MBP-TCR and mice bearing the gld/gld mutation. We believe that the answer is that the gld/+ mice are largely defective in FasL function, and thus unable to fully delete auto- aggressive cells. We also will explore the role of Fas and FasL in the pathogenesis of active EAE in MBP-TCR transgenic mice. Fourth, we will examine the role of L-selectin in the pathogenesis of EAE.

这项拨款将研究小鼠自身免疫性疾病的调节 实验性变态反应性脑脊髓炎（EAE），一种用于人类的小鼠模型 多发性硬化症，在四个不同的方式。首先，我们力求 理解为什么没有B细胞的小鼠不能完全解决它们的疾病。 我们将通过使无B细胞的小鼠与有重链的小鼠交配来解决这个问题 不能分泌的转基因，以确定抗体的产生是否 对于疾病的解决是必要的，或者如果它是抗原的存在- 特定的B细胞是至关重要的。其次，我们寻求答案 为什么携带转基因T细胞受体的小鼠特异性针对 髓鞘碱性蛋白（AC 1 -16）的N-末端乙酰化残基成为 在缺乏内源性基因排列的情况下自发患病。我们将 关于这种老鼠，我想问两个问题：首先，我们将确定 通过使用基因敲除技术来修复缺失的细胞。 当我们知道它是什么类型的细胞时，我们将把这些细胞转移到 这些老鼠，并寻找保护免受疾病，我们将尝试， 克隆这些细胞。我们还将检验自我攻击性T 细胞可以通过供应髓鞘碱性蛋白质来转换为保护性T细胞， 蛋白第三，我们将探讨自发性疾病的机制， 携带MBP-TCR的小鼠和携带MBP-TCR的小鼠的杂合后代 gld/gld突变。我们相信答案是gld/+小鼠 FasL功能有很大缺陷，因此无法完全删除自动 攻击性细胞我们还将探讨Fas和FasL在细胞凋亡中的作用。 MBP-TCR转基因小鼠中活动性EAE的发病机制。四是 研究L-选择素在EAE发病机制中的作用。