PATHOGENIC MECHANISMS IN MYASTHENIA GRAVIS

(改编自申请者的摘要)这个项目的目标是 确定MG自身抗体的致病机制 诱导异常的神经肌肉传递并设计阻断手段 这样的影响。有人建议，这些研究将提供一种 为开发抗原特异性治疗本病和 其他抗体介导的自身免疫性疾病。PEAMG由 注射针对AChR的单抗(MAbs) 为这些研究提供了实验依据。 需要检验的假说是MG的主要致病机制 补体对含AChR的突触后神经元的损伤 膜由结合的抗乙酰胆碱受体抗体激活补体启动。腹肌， 其补体激活能力已被修饰(F(ab‘)2)， 单抗片段和含有少量NO的基因工程杂交单抗 补体激活活性将在这些研究中产生和使用。 基因工程抗体将由转基因的骨髓瘤细胞产生 编码致病抗AChR V区的重组基因 单抗和缺乏补体激活活性的恒定区。这个 修饰或工程抗体诱导pEAMG或阻断EAMG的能力 由完整的抗体诱导的将进行临床、形态学、 通过电生理、化学和放射自显影分析 肌肉终板的AchR含量。

(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.