IMMUNE PROMOTION OF REMYELINATION

多发性硬化症（MS）研究中的一个重要问题是， 缺乏完全的髓鞘再生和功能恢复， 脱髓鞘疾病形态学研究表明，中枢神经系统髓鞘再生 确实发生在MS病变中，但该过程不完整。我们有 考虑了两种假设来解释没有完全髓鞘再生 在MS中，假设I是在一些脱髓鞘的 当存在时促进新髓鞘合成的损伤。 假设二 中枢神经系统髓鞘再生是初级髓鞘 但有免疫因素阻止其充分表达。 最近，我们已经表明，免疫球蛋白（Ig）可能是其中之一， 促进髓鞘再生的重要因素。我们还生成了一个 识别抗原的单克隆抗体（mAb），命名为94.03 并促进中枢神经系统髓鞘再生， vivo. 我们的第一个目标将是鉴定cDNA（指定为 髓鞘再生"REM" cDNA）编码表面蛋白， mAb 94.03识别少突胶质细胞。 我们会检查细胞 使用大鼠在COS细胞上表面表达94.03定义的表位 脑cDNA表达文库。 的功能意义 将通过将表位表达与 mRNA表达。 此外，我们将产生abs的肽的 由REM cDNA编码的衍生蛋白，以确定该抗原是 在免疫介导的髓鞘再生中很重要。 我们已经表明 使用mAb疗法消耗CD4或CD8 T细胞促进CNS 泰勒病毒慢性感染动物的髓鞘再生。在 第二个具体目标，我们将确定免疫的组成部分， 通过表征CNS抑制CNS髓鞘再生的体内反应 在TMEV感染的小鼠中， 通过基因敲除技术使其免疫缺陷在第三个具体 我们的目的是确定用mAb 94.03进行体内治疗是否具有协同作用， 以增强免疫"敲除"小鼠的CNS髓鞘再生。 这 与临床医学有重要的相关性，因为它表明， IG治疗沿着免疫抑制可增强CNS髓鞘再生。 在第四个具体目标中，我们将讨论是否观察到髓鞘再生。 在这些模型中，导致功能改善。采用了一种新技术 在小鼠中测量运动诱发和感觉诱发传导 速度，我们将确定是否治疗方法， 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潜力 在CNS。

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.