Enhancement of experimental Graves' disease by intranasal administration of a T cell epitope of the thyrotropin receptor

We previously showed that immunization of mice with murine fibroblasts transfected with the thyrotropin receptor (TSHR) and a murine major histocompatibility complex (MHC) class II molecule induces immune thyroid disease with the humoral and histological features of human Graves' disease in about 20% of mice. In this model, based on the proliferative response of T cells from hyperthyroid mice to a panel of overlapping TSHR peptides, we now demonstrate that TSHR 121-140 peptide contains an immunodominant T cell epitope. Supporting this conclusion, spleen cells from mice immunized with TSHR 121-140 peptide showed a strong proliferative response to fibroblasts transfected with the TSHR and a murine I-Ak molecule, but not either alone. Also, intranasal administration of 100 μg of TSHR 121-140 peptide led to suppressed proliferative response of lymph node cells to the peptide. Interestingly, however, administration of this peptide enhanced, rather than suppressed, the frequency and severity of Graves' disease induced by the immunization of the fibroblasts transfected with the TSHR and a murine I-Ak molecule. Spleen cells from hyperthyroid mice that were pretreated with intranasal peptide tended to produce lesser amounts of IL-4, IL-10 and IFN-gamma than those from normothyroid control mice. Although precise mechanisms of this enhancement remain to be determined, the results suggest that attempts to treat Graves' disease by intranasal administration of an immunodominant TSHR T cell epitope may aggravate, not prevent, the disease.