INTERVENTIVE STRATEGIES FOR MYASTHENIA GRAVIS

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Myasthenia gravis (MG) and its animal models Experimental Autoimmune Myasthenia Gravis (EAMG), are characterized by an ease of fatigability and relative weakness of voluntary muscles. A common feature associated with MG is T lymphocyte-dependent serum antibody responses against a self- antigen expressed by voluntary muscles, the acetylcholine receptor (AchR); the binding of anti-AChR autoantibodies to AChR at the neuromuscular junction results in the observed impairment of neuromuscular transmission. Various modalities of therapy are used to treat MG, most often immunosuppressive chemotherapy. However, the innate lack of selectivity of the drugs employed limits their usefulness. The goal of the proposed program is to identify and characterize molecular-structural targets that would allow the development of more selective immunosuppressive agents. Since MG is caused by a T cell-dependent anti-AChR antibody response, studies are to be performed to identify both B cell and T cell targets. The primary strength of the Program is that, in addition to the examination of both the B cell and T cell side of the problem, both animal models and human patient systems will be explored; this should facilitate a relatively direct path from the laboratory to the clinic. The eventual goal is to test, in MG patients, antibody-toxin conjugates (immunotoxins) with specificity for AChR-reactive lymphocytes. We are very excited to bring together, from 4 different departments, basic scientists with a history of exploring cellular and molecular immunological aspects of disease with clinicians that have direct access to both the appropriate patients as well as with the appropriate clinical setting. We believe that because of the circumstances surrounding this group of investigators, novel approaches to immune intervention in MG can be tested that would not be possible anywhere else.