Comparison of mouse and rhesus monkey models of Graves’ disease
Received:February 24, 2020  
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DOI:10. 3969 / j.issn.1005-4847. 2020. 04. 004
KeyWord:Graves’ disease; BALB/ c mice; rhesus monkey; TSHR A subunit; animal model
王悦 西安交通大学第一附属医院内分泌代谢科,西安
张萌 西安交通大学第一附属医院内分泌代谢科,西安
赵凤仪 西安交通大学第一附属医院内分泌代谢科,西安
伍丽萍 西安交通大学第一附属医院内分泌代谢科,西安
施秉银 西安交通大学第一附属医院内分泌代谢科,西安
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      Objective This study compared mouse and rhesus monkey models of Graves’ disease ( GD), particularly regarding the immunological mechanisms, and provided research tools for further novel treatment. Methods Six-week-old female BALB/ c mice were injected intramuscularly with adenovirus expressing the A-subunit of thyrotropin receptor ( TSHR) ( A-sub-Ad) three times at 3-week intervals. The animals were euthanized 4 weeks after the final injection to obtain their blood, spleen cells, thyroid glands and other organs. Three-year-old female rhesus monkeys were injected intramuscularly with A-sub-Ad five times at 3-week intervals, and sera were prepared from blood samples collected at several time points during the immunization regimen. The animals were euthanized 4 weeks after the final injection to obtain their blood, spleen cells, thyroid glands and other organs. Serum total thyroxine ( TT4) and thyrotropin receptor antibodies (TRAb) levels and thyroid morphology were detected in both the mice and rhesus monkeys to identify the thyroid function. The body weights of the mice and rhesus monkeys were recorded during the experiment as well as the resting heart rate of the rhesus monkeys. Flow cytometry was performed to detect the changes in splenic CD4 + CD25 + Foxp3 + cell proportions. Results After the final immunization, compared with the controls, the A-sub-Ad-injected mice developed significantly higher TRAb and TT4 levels [(8. 1 ± 0. 6) IU/ I vs ( 423. 1 ± 61. 4) IU/ I and ( 57. 1 ± 2. 9) μg / dL vs (96. 7 ± 13. 8) μg / dL, respectively, P< 0. 05]. Using the mean ± 2 standard deviations as the normal range, all A-sub- Ad-injected mice and rhesus monkeys showed positive TRAb levels, and 75% of the mice and half of the rhesus monkeys had increased TT4 levels. The thyroid pathology confirmed the GD-induced changes in the mice and rhesus monkeys. Different from the thyroid follicular epithelial cells in the controls, which were lowly cubic or flat, 6 / 8 mice and 3 / 6 rhesus monkeys in the model group showed obvious follicular epithelial hyperplasia with cubic or tall columnar-shaped cells, and papillary structures caused by hyperplasia protruded into the follicular cavity in part of the visual field. However, no lymphocyte infiltration occurred in the thyroids of either the mice or rhesus monkeys. In addition, the rhesus monkeys with GD lost body weight and had significantly increased resting heart rates (P< 0. 05). Flow cytometry showed decreased CD4+ CD25+Foxp3+ cell proportions in both the mouse and rhesus monkey GD groups compared with those of the control groups. Conclusions Compared with the GD rhesus monkey model, the GD mouse model showed a shorter induction time and a higher GD incidence. However, in terms of physiology and immune response, especially with GD complications, GD rhesus monkeys showed more similarities to GD patients. In future research to explore the pathogenesis and evaluate new treatments for GD, scholars can choose the appropriate research tools according to the different characteristics of the two GD animal models.
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