PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

重症肌无力的致病机制

• 批准号: 3399867
• 负责人: DAVID P RICHMAN
• 金额: $ 16.08万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3399867
• 关键词: autoantibody; autoimmune disorder; complement; electrophysiology; genetic manipulation; guinea pigs; laboratory mouse; laboratory rat; monoclonal antibody; myasthenia gravis; neuromuscular transmission; nicotinic receptors; pathologic process; protein engineering; tissue /cell culture; transfection

(Adapted from the applicant's abstract) The goal of this project is to determine the pathogenic mechanisms by which the autoantibodies in MG induce abnormal neuromuscular transmission and to devise means of blocking such effects. It is suggested that these studies would provide a groundwork for the development of antigen-specific treatments of this and other antibody-mediated autoimmune disorders. pEAMG induced by administration of monoclonal antibodies (mAbs) directed against the AChR in normal rates provides the experimental rationale for these studies. The hypothesis to be tested is that the major pathogenic mechanism in MG is complement-mediated damage to the AChR-containing post-synaptic membrane initiated by complement activation by bound anti-AChR Abs. Abs, whose complement activating capacity has been modified (F(ab')2), fragments of mAbs, and genetically engineered hybrid Abs with little of no complement activating activity will be produced and used in these studies. The engineered Abs are to be produced by myeloma cells transfected with recombinant genes which encode V regions from disease-inducing anti-AChR mAbs and constant regions which lack complement activating activity. The ability of the modified or engineered Abs to induce pEAMG or block EAMG induced by intact Abs will be assessed clinically, morphologically, electrophysiologically and by chemical and autoradiographic analysis of AChR content at muscle end plates.

（改编自申请人摘要）本项目的目标是 确定MG中自身抗体的致病机制 诱发异常神经肌肉传递并设计阻断方法 这样的效果。 建议这些研究将提供一个 为开发这种抗原特异性治疗奠定了基础， 其他抗体介导的自身免疫性疾病。 pEAMG诱导 施用针对AChR的单克隆抗体（mAb） 在正常率提供了这些研究的实验原理。 有待检验的假设是，MG的主要致病机制 是补体介导的对含有乙酰胆碱受体的突触后神经元的损伤， 通过结合的抗AChR抗体的补体激活启动膜。 艾比 其补体激活能力已被修饰（F（ab ′）2）， 单克隆抗体的片段，以及基因工程杂交抗体， 将产生补体激活活性并用于这些研究。 工程化的Ab将由转染有以下的骨髓瘤细胞产生： 编码来自疾病诱导性抗AChR的V区的重组基因 缺乏补体激活活性的mAb和恒定区。 的 修饰的或工程化的Ab诱导pEAMG或阻断EAMG的能力 将在临床上，形态学上， 电生理学和化学和放射自显影分析 肌肉终板AChR含量。