The overall goal of this project is to provide an analysis of the idiotypic network in myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG). We hope that such an analysis will: 1) further the understanding of the idiotypic network in general, 2) examine its functioning in a specific, well-defined system, and, 3) make an advance along the road to the development of new treatments for MG, and other autoimmune diseases. We have developed a large library of monoclonal antibodies (mAbs) directed against the acetylcholine receptor (AChR), the antigen in this disease. Such mAbs represent sources of pure idiotype (Id) with which to produce antiidiotypic antibodies (antiId). We already have available 17 antiId mAbs. These, and others to be developed during the course of this project, will be used to analyze the idiotypic repertoire of anti-AChR antibodies in the serum of patients with MG and animals with EAMG. Special attention will be paid to the identification of public Ids, those present in a large number of individuals, and especially those that are dominant, i.e., represent a significant portion of the total anti-AChR response. Since in other systems, the levels of such Ids, and, at times, the entire antibody response, can be manipulated by injection of antiId, we will continue experiments already underway in which antiId injections prior to immunization with AChR have reduced the severity of the EAMG that develops. Effort will be put into the development of strategies to similarily modify EAMG after immunization. In addition, work will continue on the production of mAbs from purified blood lymphocytes of MG patients. The methods to be used in this project include hybridoma production, enzyme linked immunoassays for Id and antiId, assessment of EAMG by clinical observation, electromyography, intracellular recordings, and determination of AChR content in muscle.
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