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.