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 disease. T cells reactive to a dominant peptide α 146-162 of acetylcholine receptor (AChR) α subunit participate in murine MG pathogenesis. To suppress the autoimmune response to AChR, a high dose of α 146-162 peptide in IFA was administered parenterally as a tolerogen, after 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 proliferative response to AChR and its dominant 146-162 and subdominant α182-198 peptides through epitope spread. Administration of α146-162 peptide in IFA after the primary immune response to AChR also significantly suppressed the serum anti-AChR Ab of the lgG2b isotype and clinical incidence of MG in C57BL/6 mice. Furthermore, the production of IFN-γ, IL-2, and IL-10 cytokines by AChR, α146-162, and α182-198 peptide-reactive cells was suppressed by α146-162 peptide tolerance, and the epitope spread observed could be attributed to the reduction in the above cytokine production. Therefore, AChR T cell-dominant peptide tolerance could be adapted in the Ag-specific therapy of MG.