Contrasting activities of thyrotropin receptor antibodies in experimental models of Graves' disease induced by injection of transfected fibroblasts or deoxyribonucleic acid vaccination

The development of experimental models of autoimmune hyperthyroid Graves' disease has proved a difficult challenge, but recently two novel methods have led to their successful development in mice. We describe our studies on replicating the adjuvant modified, human TSH receptor (TSHR) and major histocompatibility complex class II transfected fibroblast injection system, and the plasmid DNA vaccination method as models resembling the human disorder. The fibroblast injection model in female AKR/N (H-2k) mice led to 70% of the animals developing thyroid-stimulating antibodies and their thyroid glands showed large goiters with histological features of thyroid cell activation characteristic of Graves' glands. Consistent with the clinical homolog, there was no inflammatory cell infiltrate of the thyroid gland. Detailed studies on the anti-TSHR antibodies such as thyroid-stimulating blocking antibody, antibodies to the native TSHR by flow cytometry, and TSH-binding inhibiting Ig showed that they were heterogeneous and did not correlate with disease activity, thus resembling those present in patients with Graves' disease. In contrast, the plasmid DNA vaccination model in female BALB/c (H-2d) mice led to the generation of low levels of anti-TSHR antibodies by flow cytometry, which were undetectable for thyroid-stimulating antibodies, TSH-stimulating blocking antibodies, and TSH-binding inhibiting Ig activity. Moreover, this model too was not accompanied by lymphocytic cell infiltration. The data demonstrate the high incidence of hyperthyroid disease induced in the adjuvant modified, transfected fibroblast model in AKR/N mice to allow pathological mechanisms of disease to be studied.