Endocrine Abstracts

Background: Graves’ disease (GD) is an autoimmune disease caused by autoantibody targeting the thyrotropin receptor (TSHR) in the thyroid gland, resulting in hyperthyroidism with an annual incidence of 15 to 80/100,000 people worldwide. Current mainstream treatments for GD include aggressive treatment with radioiodine and thyroidectomy or unspecific immune-modulating therapy with glucocorticoids, antithyroid medications or anti-CD20 antibodies like Rituximab. Therefore, our current focus is on the application of an antigen-specific immune modulation, namely peptide therapy using altered peptide ligands, which potentially reduce inflammatory responses via induction of immune tolerance in GD patients.

Methods: A mouse model that mimics symptoms of human GD was established by monthly immunization of adenovirus that produces TSHR A subunit protein (Ad-TSHR) and Ad-GFP adenovirus as control for 35 weeks. Herein, the therapeutic peptide P19 which was selected from potential antigens via in silico and in vitro evaluation was applied monthly in the diseased mice starting from 11 weeks after the first Ad-TSHR immunization to investigate its therapeutic effect. The study was achieved by conduction of typical clinical examinations including macro- and microscopic observation of affected organs i.e. thyroid, eye and heart, along with determination of thyroxine (T4) and anti-TSHR autoantibody level.

Results: Macroscopic examination revealed clearly enlarged thyroid glands in mice that had received nine immunizations of Ad-TSHR compared to the native and Ad-GFP mouse groups. On the contrary, diseased mice receiving P19 treatment had a significant decrease in thyroid size (P>0.05). Moreover, scalloped colloid and collapsed follicles were prominent in the Ad-TSHR mouse group under microscopic investigation, yet the histological presentation was markedly improved in the P19-treated group. Further analysis showed a remarkable reduction on T4 after two administrations of P19 (P>0.05) and the reduction was well maintained by means of P19 till the end of experiment. It indicated a significant amelioration of hyperthyroidism through application with P19. Autoantibody against TSHR as an essential clinical parameter was also tested and the result showed a concurrent decline of T4 and anti-TSHR autoantibody in a well correlated fashion with P19 treatment (P>0.05). Subsequently, the P19 application also represented a mild improvement on both orbital fibrosis and heart function in the diseased mice.

Conclusion: The therapeutic peptide P19 we identified revealed an anticipated benefit in the mouse model of Graves’ disease with relevant clinical improvement. Thus, the results encourage further insightful exploration of this therapeutic application as a potential treatment for Graves’ disease.