Lessons from mouse models of Graves' disease

Abstract

Graves' disease (GD) is an autoimmune condition with the appearance of anti-TSH receptor (TSHR) autoantibodies in the serum. The consequence is the development of hyperthyroidism in most of the patients. In addition, in the most severe cases, patients can develop orbitopathy (GO), achropachy and dermopathy. The central role of the TSHR for the disease pathology has been well accepted. Therefore immunization against the TSHR is pivotal for the creation of in vivo models for the disease. However, TSHR is well preserved among the species and therefore the immune system is highly tolerant. Many differing attempts have been performed to break tolerance and to create a proper animal model in the last decades. The most successful have been achieved by introducing the human TSHR extracellular domain into the body, either by injection of plasmid or adenoviruses. Currently available models develop the whole spectrum of Graves' disease-autoimmune thyroid disease and orbitopathy and are suitable to study disease pathogenesis and to perform treatment studies. In recent publications new immunomodulatory therapies have been assessed and also diseaseprevention by inducing tolerance using small cyclic peptides from the antigenic region of the extracellular subunit of the TSHR.

Fig. 1

Immunization against the TSHR was realized by inducing in vivo-expression of the TSHR by using different approaches

Fig. 2

Treatment with fingolimod in a preclinical mouse model: animals were treated with the first immunisation during disease onset (preventive treatment; TSHR +prev) or after the last immunisation with TSHR extracellular coding plasmid (therapy in the state of fully developed disease; TSHR +ther). Results of different parameters were combined and analyzed by Z-scoring for autoimmune hyperthyroidism (GD—including results for fT4, TSAb [stimulating anti-TSH-receptor antibodies], bodyweight, body temperature, CD3 infiltration of the thyroid), orbitopathy (GO—including brown fat content, CD3 infiltration in the orbital tissues, Hyaluronan acid content) or total disease (GD + GO). Percentages of mice that have developed either no (Z-score < 0, blue), mild (Z-score > 0 but < 1, red) or moderate/severe (Z-score > 1, yellow) disease are indicated