IMMUNE PROMOTION OF REMYELINATION

免疫促进髓鞘再生

• 批准号: 2445745
• 负责人: MOSES RODRIGUEZ
• 金额: $ 25.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-07 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2445745
• 关键词: T lymphocyte; autoradiography; complementary DNA; developmental neurobiology; evoked potentials; immunoperoxidase; in situ hybridization; laboratory mouse; molecular cloning; monoclonal antibody; murine encephalomyelitis virus; myelin; myelination; neural conduction; neuroimmunomodulation; neuropharmacology; oligodendroglia; passive immunization; protein biosynthesis; saxitoxin; sodium channel; spinal cord; surface antigens; virus diseases

An important question in multiple sclerosis (MS) research is why there is absence of full remyelination and functional recovery following demyelinating disease. Morphologic studies suggest that CNS remyelination does occur in the MS lesion but the process is incomplete. We have considered two hypotheses to explain the absence of full remyelination in MS. Hypothesis I is that there are factors within some demyelinated lesions which when present promote new myelin synthesis. Hypothesis II is that CNS remyelination is the normal consequence of primary myelin injury but there are immune factors which prevent its full expression. Most recently we have shown that immunoglobulins (Igs) may be one of the important factors that promote remyelination. We have also generated a monoclonal antibody (mAb) designated 94.03 which recognizes an antigen on the surface of oligodendrocytes and promotes CNS remyelination in vivo. Our first goal will be to identify the cDNA (designated remyelination "REM" cDNA) encoding the surface protein on oligodendrocytes recognized by mAb 94.03. We will screen for cell surface expression on COS cells of the 94.03 defined epitope using a rat brain cDNA expression library. The functional significance of the identified clones will be verified by correlating epitope expression with mRNA expression. In addition, we will generate abs to peptides of the derived protein encoded by REM cDNA to determine that this antigen is important in immune-mediated remyelination. We have shown previously that depletion of CD4 or CD8 T cells using mAb therapy promotes CNS remyelination in animals chronically infected with Theiler's virus. In the second specific aim we will determine the components of the immune response in vivo which inhibit CNS remyelination by characterizing CNS remyelination and virus persistence in TMEV-infected mice that have been rendered immune deficient by knockout technology. In the third specific aim we will determine whether in vivo treatment with mAb 94.03 synergizes to enhance CNS remyelination in immune "knockout" mice. This has important relevance to clinical medicine because it would indicate that Ig treatment along with immunosuppression may enhance CNS remyelination. In the fourth specific aim we will address whether remyelination observed in these models results in functional improvement. Using a new technique in the mouse to measure motor-evoked and sensory-evoked conduction velocities, we will determine whether the therapeutic approaches to promote remyelination improves conduction. These experiments have the potential to elucidate new strategies for the promotion of remyelination in the CNS.

多发性硬化症(MS)研究中的一个重要问题是为什么 之后是否没有完全的髓鞘再生和功能恢复 脱髓鞘疾病。形态研究提示中枢神经系统髓鞘再分化 确实发生在多发性硬化症的病变中，但这个过程是不完整的。我们有 考虑了两个假说来解释没有完全的髓鞘再生 在女士的假设中，我是说里面有一些脱髓鞘的因素 当损伤出现时会促进新髓鞘的合成。假设II 中枢神经系统髓鞘再分化是初级髓鞘的正常结果 但有免疫因素阻止了它的充分表达。 最近，我们发现免疫球蛋白(Ig)可能是 促进髓鞘再生的重要因素。我们还生成了一个 识别抗原的单抗(MAb)，命名为94.03 表达于少突胶质细胞表面，促进中枢神经系统髓鞘再生 活着。我们的第一个目标是鉴定cDNAs(指定为 编码表面蛋白的重髓鞘“REM”c DNA) MAb94.03识别的少突胶质细胞。我们会筛查手机 利用大鼠在COS细胞表面表达94.03表位 脑基因表达文库。的功能意义 识别的克隆将通过将表位表达与 M RNA的表达。此外，我们还将产生abs到多肽 用REM cDNA编码的衍生蛋白确定该抗原是 在免疫介导的重新髓鞘形成过程中起重要作用。我们之前已经展示过 用单抗治疗去除CD4或CD8T细胞可促进中枢神经系统 慢性感染泰勒氏病毒的动物的再髓鞘形成。在……里面 第二个具体目标是我们将确定免疫的成分 通过表征中枢神经系统抑制中枢神经系统再髓鞘形成的体内反应 TMEV感染小鼠的再髓鞘形成和病毒持久性 通过基因敲除技术导致免疫缺陷。在第三个具体项目中 目的我们将确定单抗94.03在体内治疗是否具有协同作用 增强免疫基因敲除小鼠中枢神经系统髓鞘再生。这有 对临床医学很重要，因为这将表明 免疫球蛋白治疗联合免疫抑制可促进中枢神经系统髓鞘再生。 在第四个具体目标中，我们将讨论是否观察到重新髓鞘形成 在这些模型中会导致功能的改善。使用一种新技术 在小鼠身上测量运动诱发和感觉诱发的传导 速度，我们将确定治疗方法是否 促进髓鞘再生改善传导。这些实验具有 阐明促进髓鞘再生的新策略的可能性 在中枢神经系统。