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王悦,张萌,赵凤仪,伍丽萍,施秉银.小鼠及猕猴 Graves 病动物模型的比较研究[J].中国实验动物学报,2020,28(4):455~462.
小鼠及猕猴 Graves 病动物模型的比较研究
Comparison of mouse and rhesus monkey models of Graves’ disease
投稿时间:2020-02-24  
DOI:10. 3969 / j.issn.1005-4847. 2020. 04. 004
中文关键词:  Graves 病  BALB/ c 小鼠  猕猴  TSHR A 亚单位  动物模型
英文关键词:Graves’ disease  BALB/ c mice  rhesus monkey  TSHR A subunit  animal model
基金项目:
作者单位E-mail
王悦 西安交通大学第一附属医院内分泌代谢科,西安 710061 shelly1021@ 126.com 
张萌 西安交通大学第一附属医院内分泌代谢科,西安 710061 869083468@ qq.com 
赵凤仪 西安交通大学第一附属医院内分泌代谢科,西安 710061  
伍丽萍 西安交通大学第一附属医院内分泌代谢科,西安 710061  
施秉银 西安交通大学第一附属医院内分泌代谢科,西安 710061 shibingy@ 126.com 
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中文摘要:
      目的 本研究旨在从 Graves 病(Graves’ disease,GD)免疫相关机制出发,通过比较我们既往研究中 小鼠及猕猴 GD 动物模型,探讨不同动物 GD 模型特点差异,并基于不同动物模型的特点,为日后免疫治疗新方法 提供研究工具。 方法 利用表达促甲状腺素受体(TSHR)A 亚单位的重组腺病毒肌肉注射 BALB/ c 小鼠,每三周 1 次,共 3 次。 利用同样的重组腺病毒肌肉注射猕猴,基于小鼠病毒剂量通过体重和体表面积换算出猕猴的病毒剂 量,每三周 1 次,共 5 次。 于末次免疫后四周安乐死小鼠和猕猴,收集外周血、甲状腺、脾等组织测定总甲状腺素 TT4、促甲状腺激素受体抗体 TRAb 及免疫学相关指标。 结果 小鼠造模组( n = 8) TRAb 水平较对照组显著增高 [(8. 1 ± 0. 6)IU/ I vs 423. 1 ± 61. 4) IU/ I], 其中有 6 只小鼠的 TT4 水平明显增高,整体 T4 水平显著高于对照组 [(57. 1 ± 2. 9)μg / dL vs(96. 7 ± 13. 8)μg / dL, P < 0. 05],GD 甲亢发生率为 75%。 猕猴造模组(n= 6)中有 3 只猕 猴的 TT4 和 FT4 水平均明显增高,甲亢发生率为 50%。 甲状腺病理中,小鼠(6 / 8)及猕猴(3 / 6)造模组中均出现了 滤泡上皮明显增生,呈立方状或高柱状。 流式细胞学分析显示,猕猴造模组的外周血和脾中的 Treg 细胞比例均显 著低于对照组(P< 0. 05),这一结果与小鼠造模组的脾中 Treg 细胞比例结果一致(P< 0. 05)。 此外,造模组的猕 猴还出现了体重的下降(P < 0. 05)和静息心率的上升(P< 0. 05)。 结论 与猕猴 GD 模型相比,小鼠模型 GD 甲亢的诱导时间更短,发生率更高,但 GD 猕猴基础生理生化指标和免疫相关指标中显示出更多的与人类 GD 患者类 似的表现及机制。 在日后探索 GD 发病机制及评估新治疗方案的研究中,我们可以根据两种动物 GD 模型的不同 特点选择更合适的研究工具。
英文摘要:
      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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