Myasthenia gravis (MG) is an autoimmune disease in which neuromuscular transmission is impaired, probably due to circulating antibodies directed against the acetylcholine receptor (AChR) found in the postsynaptic membrane of the neuromuscular junction. Injection of purified AChR into rats produces chronic symptoms very similar to those demonstrated by MG patients. The goal of this project is to develop a successful immunotherapeutic approach to the treatment of MG using the rat model, experimental autoimmune myasthenia gravis (EAMG). Emphasis will be on the elimination of the clones of lymphocytes capable of reacting with the AChR by treatment with synthetic hybrid toxins composed of the active peptide of the toxin, ricin, covalently linked to a binding moiety which will direct the toxin specifically to the autoreactive cells. This investigation will be conducted at two levels: 1) Delete autoreactive clones in vitro and in vivo by treatment with antigen coupled to the A-chain of ricin; i.e., ricin A-chain will be covalently coupled to purified AChR which will then be used to delete (kill) clones of B lymphocytes which express antigen receptors and therfore reactivity for AChR, and 2) Delete autoreactive clones in vitro and in vivo by treatment with anti-idiotypic antibodies coupled to antibodies reactive with the clonally expressed determinants (idiotypes) associated with the antigen binding sites of receptors on AChR-reactive B lymphocytes, will be used to delete (kill) those AChR-specific cells. The ultimate goal of this study is to use these specific immunotoxic agents (perhaps in conjunction with non-specific immunosuppressive drugs) to induce long-term remissions of EAMG symptoms demonstrated by animals with progressive disease.
