TOWARDS IDENTIFICATION OF A TOLERAGEN FOR THE TREATMENT OF MYASTHENIA GRAVIS.

Mary-Ann Campbell, Korey Chong, Guang Luo, Joddi Preclaro, David Ramirez, Kimberly Victor and Matthew Linnik.

La Jolla Pharmaceutical Company, San Diego, CA 92121

In myasthenia gravis (MG), autoantibody-mediated crosslinking of nicotinic acetylcholine receptors (AChR) at the neuromuscular junction results in an increased rate of AChR internalization and degradation. Loss of AChR results in fatigability and weakness of the skeletal muscles. Because damage to the neuromuscular junction is antibody-mediated, tolerization of AChR-specific B lymphocytes might be expected to ameliorate disease.

The antibody response to AChR is T cell-dependent, thus crosslinking of AChR-specific B cells with a mimetic of the AChR that cannot be processed for presentation to T helper cells should result in elimination of the anti-AChR response.

Using an in vitro assay system for antibody-mediated AChR downmodulation, we are in the process of identifying sequences that can inhibit the activity of MG patient sera. These sequences will then be used to construct toleragens for preclinical testing in the rat experimental autoimmune myasthenia gravis model.

Presented at the Keystone Symposium, B Lymphocyte Biology and Disease, Taos, New Mexico, Feb. 8-14, 1999.