Effect of Halofuginone on the Pathogenesis of Autoimmune Thyroid Disease in Different Mice Models
Effect of Halofuginone on the Pathogenesis of Autoimmune Thyroid Disease in Different Mice Models
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常酮对不同小鼠模型自身免疫性甲状腺疾病发病机制的影响
DOI：
10.2174/1871530317666170424101256
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发表时间：
2017-01-01
影响因子：
1.9
通讯作者：
Li, Yushu
中科院分区：
文献类型：
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作者：
Hou, Xin;Zhou, Jin;Li, Yushu
目的：观察halofuginone （HF）治疗自身免疫性甲状腺疾病（AITDs）的疗效，并探讨其作用机制。方法：用表达TSH受体A亚基（Ad-TSHR289）的腺病毒免疫BALB/c雌性小鼠，建立Graves病（GD）模型。Ad-TSHRA(+) HF组和AdTSHRA(+) DMSO组分别腹腔注射HF或DMSO。自身免疫性甲状腺炎（AIT）组由女性NOD组成。在研究期间，H-2h4小鼠在饮用水中给予NaI，并每天腹腔注射DMSO。AIT/HF组由女性NOD组成。H-2h4小鼠饮水给予NaI，每日腹腔注射HF。流式细胞术检测脾脏Th17细胞、Tregs细胞和Bregs细胞的表达频率。IL-17、叉头盒P3 （Foxp3）、ROR mRNA水平。实时荧光定量PCR检测t和IL-10。结果：在Ad-TSHRA(+) DMSO组和Ad-TSHRA(+) HF组，15只小鼠中有10只血清T4和TSAb水平高于对照平均水平3 SD。HF组GD模型CD4+ CD25(+) Foxp3(+) T淋巴细胞数量较DMSO组显著升高（P < 0.05）。与Ad-TSHRA(+) DMSO组相比，Ad-TSHRA(+) HF组Foxp3 mRNA水平显著升高（P < 0.05）。然而，在Ad-TSHRA(+) HF和Ad-TSHRA(+) DMSO组之间，CD4(+) IL-17+ T细胞亚群的丰度和ROR γ T mRNA表达水平均无显著差异（P < 0.05）。与AIT组相比，AIT/HF组血清TgAb滴度显著降低（P < 0.01）。各组间CD4（+）、CD25（+）、Foxp3(+) T淋巴细胞数量及Foxp3 mRNA水平差异均无统计学意义（P < 0.05）。而CD4(+) IL-17(+) T细胞数量及IL-17和ROR mRNA水平的变化。与未处理的ait诱导小鼠相比，hf处理小鼠的t均显著升高（P < 0.05）。结论：HF治疗可通过降低CD4(+) IL-17(+) T细胞数量，显著降低AIT发生率。
Objective: Our objectives were to investigate the therapeutic effect of halofuginone (HF) in the treatment of autoimmune thyroid diseases (AITDs) and explore its underlying mechanism of action.Methods: The Graves' disease (GD) model was generated by immunizing female BALB/c mice with adenovirus expressing the TSH receptor A subunit (Ad-TSHR289). The Ad-TSHRA(+) HF and AdTSHRA(+) DMSO groups were injected intraperitoneally with HF or the vehicle control (DMSO), respectively. The autoimmune thyroiditis (AIT) group consisted of female NOD. H-2h4 mice that were administered NaI in the drinking water and intraperitoneally injected daily with the vehicle control (DMSO) during the study period. The AIT/HF group consisted of female NOD. H-2h4 mice that were administered NaI in the drinking water and intraperitoneally injected daily with HF. The frequencies of splenic Th17 cells, Tregs and Bregs were determined by flow cytometry. The mRNA levels of IL-17, forkhead box P3 (Foxp3), ROR.t and IL-10 were determined by real-time PCR.Results: In both Ad-TSHRA(+) DMSO and Ad-TSHRA(+) HF groups, 10 out of 15 mice displayed serum T4 and TSAb levels above 3 SD beyond the mean control levels. The number of CD4+ CD25(+) Foxp3(+) T lymphocytes in the GD model was significantly increased in the HF group compared with the DMSO group (P < 0.05). The mRNA level of Foxp3 was significantly increased in the Ad-TSHRA(+) HF group compared with the Ad-TSHRA(+) DMSO group (P < 0.05). However, neither the abundance of CD4(+) IL-17+ T cell subpopulation nor the mRNA expression level of ROR gamma t differed significantly between the Ad-TSHRA(+) HF and Ad-TSHRA(+) DMSO groups (P > 0.05). The serum TgAb titer was significantly reduced in the AIT/HF group compared with the AIT group (P < 0.01). The differences in the number of CD4(+) CD25(+) Foxp3(+) T lymphocytes and the mRNA levels of Foxp3 between the AIT/HF and AITgroups were not significant (P > 0.05). However, the number of CD4(+) IL-17(+) T cells and the mRNA levels of IL-17 and ROR.t were significantly increased in HF-treated mice compared with the non-treated AIT-induced mice (P < 0.05).Conclusion: Treatment with HF significantly decreased the incidence of AIT by decreasing the number of CD4(+) IL-17(+) T cells.