PREVENTION OF EXPERIMENTAL MYASTHENIA-GRAVIS BY NASAL ADMINISTRATION OF SYNTHETIC ACETYLCHOLINE-RECEPTOR-T EPITOPE SEQUENCES

T cell tolerization prevents and improves T cell-mediated experimental autoimmune diseases. We investigated here whether similar approaches could be used for antibody (Ab)-mediated autoimmune diseases, Myasthen ia gravis, caused by IgG Ab against muscle acetylcholine receptor (ACh R), is perhaps the best characterized of them. We used an animal model , experimental myasthenia gravis induced in C57Bl/6 mice by immunizati on with Torpedo acetylcholine receptor (TAChR), to demonstrate that na sal administration of synthetic sequences of the TAChR alpha-subunit-f orming epitopes recognized by anti-TAChR CD4(+) T helper cells (residu es alpha 150-169, alpha 181-200, and alpha 360-378), given before and during immunization with TAChR, causes decreased CD4(+) responsiveness to those epitopes and to TAChR, reduced synthesis of anti-TAChR Ab, a nd prevented experimental myasthenia gravis. These effects were not in duced by nasal administration of synthetic epitopes of diphtheria toxi n. Secretion of IL-2, 1L-4, and IL-10 by spleen T cells from TAChR imm unized mice, in response to challenge with TAChR in vitro, indicated t hat in sham-tolerized mice only Th1 cells responded to TAChR, while pe ptide-treated mice had also an AChR-specific Th2 response. The TAChR p eptide treatment induced also in vitro anergy to the TAChR of the sple en T cells, which was reversed by IL-2.