Myasthenia gravis (MG) is an important human disease characterized by muscle weakness and fatigue. These symptoms are caused by the action of antibodies against acetylcholine receptor (AChR) located on the postsynaptic membrane of the neuromuscular junction. The production of these antibodies is under the control of AChR- specific T lymphocytes which recognize peptide fragments of AChR complexed with host major histocompatibility complex (MHC) class II molecules. In an animal model of MG induced in mice by immunization with AChR, the specific helper T lymphocytes are predominantly directed at a single peptide, amino acid residues 146-162 of the AChR alpha subunit. However, at least three other subdominant peptides are also recognized. Analogs of the AChR alpha 146-162 peptide containing discrete substitutions act as antagonists of specific T cell activation. Such altered peptide ligands (APL) have been proposed as specific immunotherapy for various autoimmune diseases which may avoid the side effects of current immunosuppressive regimens. In this project, APL antagonists will be developed and used as probes of T cell involvement and T cell-B interaction in MG with the ultimate goal of preventing and treating MG in animals.
The specific aims are: (1) optimize delivery of inhibitory APL signals to the immunodominant T cells recognizing the alpha 146-162 peptide. Planned studies include modification of the APL as well as inhibition of other T cell signals; (2) utilize APL as probes of antigen-specific T cell populations in EAMG. Studies in this aim are designed to dissect the role of different T cells in the production of pathogenic autoantibodies and to design rational therapeutic strategies. MG is an important target disease for testing novel specific immunotherapies. The autoantigen AChR is immunologically complex and multiple strategies might be necessary for effective therapy. MG involves T cell-B cell interaction and is a prototype of antibody-mediated autoimmune disease. The target antigen of human MG is known and results from the animal model may be readily translated into the clinical setting. Because of these properties, studies of specific peptide inhibition of MG should be broadly informative.
