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: 6340672
• 负责人: CHARLES A JANEWAY
• 金额: $ 13.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6340672
• 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.

这笔赠款将检验对小鼠自身免疫性疾病的调控。 实验性变态反应性脑脊髓炎(EAE) 疾病多发性硬化症，有四种不同的方式。首先，我们寻求 理解为什么没有B细胞的小鼠无法完全解决他们的疾病。 我们将通过将无B基因的小鼠培育成具有重链的小鼠来解决这一问题 无法分泌的转基因，以确定抗体的产生是否 对于疾病的解决是必要的，或者如果是抗原的存在- 特定的B细胞是至关重要的。第二，我们寻求一个答案 为什么小鼠携带特异性的转基因T细胞受体？ 髓鞘碱性蛋白的N-末端乙酰化残基(AC1-16)成为 在没有内源性基因排列的情况下自发性患病。我们会 问两个关于这类老鼠的问题：第一，我们将确定 通过使用基因敲除技术来修复缺失的一个或多个细胞。 当我们知道是什么类型的细胞(S)时，我们会将这些细胞转移到 并寻找对疾病的保护，我们将尝试 克隆这样的细胞。我们还将检验自我攻击性T细胞的假设 细胞可以通过喂食髓鞘碱性蛋白而转变为保护性T细胞 蛋白。第三，我们将探索自发性疾病的发病机制。 携带MBP-TCR的小鼠和携带MBP-TCR的小鼠的杂合子代 GLD/GLD突变。我们认为答案是GLD/+小鼠是 FasL功能有很大缺陷，无法完全删除自动- 具有侵略性的细胞。我们还将探讨Fas和FasL在 MBP-TCR转基因小鼠活动性EAE的发病机制。第四，我们将 探讨L-选择素在EAE发病机制中的作用。