TOLERANCE TO A DOMINANT T-CELL EPITOPE IN THE ACETYLCHOLINE-RECEPTOR MOLECULE INDUCES EPITOPE SPREAD AND SUPPRESSES MURINE MYASTHENIA-GRAVIS

Myasthenia gravis (MG) is a T cell-dependent, Ab-mediated autoimmune d isease, T cells reactive to a dominant peptide alpha 146-162 of acetyl choline receptor (AChR) a subunit participate in murine MG pathogenesi s. To suppress the autoimmune response to AChR, a high dose of alpha 1 46-162 peptide in IFA was administered parenterally as a tolerogen, af ter the development of a primary T cell immune response to AChR, This form of AChR T cell peptide tolerance suppressed the in vitro T cell p roliferative response to AChR and its dominant alpha 146-162 and subdo minant alpha 182-198 peptides through epitope spread, Administration o f alpha 146-162 peptide in IFA after the primary immune response to AC hR also significantly suppressed the serum anti-AChR Ab of the IgG2b i sotype and clinical incidence of MG in C57BL/6 mice, Furthermore, the production of IFN-gamma, IL-2, and IL-10 cytokines by AChR, alpha 146- 162, and alpha 182-198 peptide-reactive cells was suppressed by alpha 146-162 peptide tolerance, and the epitope spread observed could be at tributed to the reduction in the above cytokine production, Therefore, AChR T cell-dominant peptide tolerance could be adapted in the Ag-spe cific therapy of MG.