Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease

We performed genetic immunization of outbred NMRI mice, using a cDNA encodi ng the human thyrotropin receptor (TSHr). All mice produced antibodies capa ble of recognizing the recombinant receptor expressed at the surface of sta bly transfected Chinese hamster ovary (CHO) cells, and sera from most of th e immunized mice blocked TSH-dependent stimulation of cAMP accumulation in cells expressing the TSHr. Five out of 29 female mice showed sign of hypert hyroidism including elevated total T4 and suppressed TSH levels. The serum of these mice contained thyroid-stimulating activity, as measured in a clas sic assay using CHO cells expressing recombinant TSHr. In contrast, only 1 male out of 30 had moderately elevated serum total T4 with undetectable TSH values. The hyperthyroid animals had goiters with extensive lymphocytic in filtration, characteristic of a Th2 immune response. In addition, these ani mals displayed ocular signs reminiscent of Graves' ophthalmopathy, includin g edema, deposit of amorphous material, and cellular infiltration of their extraocular muscles. Our results demonstrate that genetic immunization of o utbred NMRI mice with the human TSHr provides the most convincing murine mo del of Graves' disease available to date.