PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

重症肌无力的致病机制

• 批准号: 3399860
• 负责人: DAVID P RICHMAN
• 金额: $ 19.04万
• 依托单位: UNIVERSITY OF CHICAGO
• 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 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3399860
• 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.

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