Regulation of Graves' hyperthyroidism with naturally occurring CD4+CD25+ regulatory T cells in a mouse model
Regulation of Graves' hyperthyroidism with naturally occurring CD4+CD25+ regulatory T cells in a mouse model
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DOI：
10.1210/en.2005-1024
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发表时间：
2006-05-01
期刊：
影响因子：
4.8
通讯作者：
Nagayama, Y
中科院分区：
文献类型：
--
作者：
Saitoh, O;Nagayama, Y
用编码TSH受体的重组腺病毒（TSHR）反复免疫易感小鼠，可有效诱导Graves甲亢。本研究旨在评价自然存在的CD 4（+）CD 25（+）调节性T细胞在抵抗性C57 BL/6和易感性BALB/c小鼠Graves甲亢发生中的作用。CD 4（+）CD 25（+）T细胞的耗竭使一些C57 BL/6小鼠对甲状腺功能亢进症的诱导敏感。因此，在用表达TSHR A亚单位的腺病毒（AdTSHR 289）免疫的CD 4（+）CD 25（+）T细胞耗尽的C57 BL/6小鼠中，30%发生甲状腺功能亢进，而仅用AdTSHR 289免疫的小鼠中，0%发生甲状腺功能亢进。这种免疫操作也增加了易感BALB/c小鼠的疾病严重程度，这反映在CD 4（+）CD 25（+）T细胞耗竭导致平均T4水平显著增加。CD 4（+）CD 25（+）T细胞耗竭的免疫增强效应似乎可归因于甲状腺刺激抗体产生的增加和/或甲状腺阻断抗体合成的减少，但不是对辅助性T细胞1或2的免疫偏离。有趣的是，与BALB/c小鼠不同，一些甲状腺功能亢进的C57 BL/6小鼠表现出一些甲状腺内淋巴细胞浸润伴滤泡破坏。这些结果表明，CD 4（+）CD 25（+）T细胞在腺病毒-TSHR诱导的Graves'甲亢的疾病易感性和严重性中起作用。总的来说，效应和调节T细胞之间的不平衡似乎是至关重要的格雷夫斯病的发病机制。
Graves' hyperthyroidism can be efficiently induced in susceptible mouse strains by repeated immunization with recombinant adenovirus coding the TSH receptor (TSHR). This study was designed to evaluate the role(s) played by naturally occurring CD4(+)CD25(+) regulatory T cells in the development of Graves' hyperthyroidism in resistant C57BL/6 and susceptible BALB/c mice. Depletion of CD4(+)CD25(+) T cells rendered some C57BL/6 mice susceptible to induction of hyperthyroidism. Thus, hyperthyroidism developed in 30% of the CD4(+)CD25(+) T cell-depleted C57BL/6 mice immunized with adenovirus expressing the TSHR A-subunit (AdTSHR289) vs. 0% of those immunized with AdTSHR289 alone. This immunological manipulation also enhanced disease severity in susceptible BALB/c mice, as reflected by a significant increase in mean T4 levels by CD4(+)CD25(+) T cell depletion. The immunoenhancing effect of CD4(+)CD25(+) T cell depletion appears to be attributable to an increase in thyroid-stimulating antibody production and/or a decrease in thyroid-blocking antibody synthesis, but not immune deviation to either T helper 1 or 2 cells. Interestingly, unlike BALB/c mice, some hyperthyroid C57BL/6 mice showed some intrathyroidal lymphocytic infiltration with follicular destruction. These results indicate that CD4(+)CD25(+) T cells play a role in disease susceptibility and severity in adenovirus-TSHR-induced Graves' hyperthyroidism. Overall, the imbalance between effector and regulatory T cells appears to be crucial in the pathogenesis of Graves' disease.