Background

BALB/c mice which received long-term immunizations of adenovirus (Ad) expressing thyrotropin receptor A-subunits (TSHR) developed stable Graves’ disease (GD). TSHR-derived cyclic peptide 19 (P19) was identified as effective therapy in this model.

Methods

In Ad-TSHR mice, we investigated shorter disease intervals up to 4 months for histological alterations of the orbits, fine tuning of anti-TSHR antibodies (Ab) and free thyroxine (fT4) hormone levels by using novel detection methods in an independent laboratory. Therapy (0.3 mg/kg P19 or vehicle) was given intravenously after the fourth Ad-TSHR immunization (week 11) and continued until week 19.

Results

Thyrotropin binding inhibitory immunoglobulins (TBII, bridge immunoassay), blocking (TBAb) and stimulating (TSAb) TSHR-Ab (both cell-based bioassays) and serum levels of fT4 were significantly elevated at week 11 in Ad-TSHR-immunized mice versus none in control mice. For the first time, TSAb, TBAb, and thyroperoxidase-Ab were detected in 17 of 19, 12/19 and 6/19 Ad-TSHR immunized mice, respectively at week 21. Also, for the first time, this study showed that P19 treatment markedly reduced serum TBII (p < 0.0001), serum fT4 (p = 0.02), and acidic mucins and collagen content in the orbital tissue of Ad-TSHR-immunized mice.

Conclusion

P19 significantly improved thyroid function, confirming previous results in an independent second laboratory. A relevant shift of anti-TSHR antibody subpopulations in response to P19 therapy may help explain its immunological effects. Moreover, P19 exerted a beneficial effect on mucine and collagen content of orbital tissue. Hence, P19 offers a potential novel therapeutic approach for GD and associated orbitopathy.

中文翻译：

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环肽显着改善长期格雷夫斯病小鼠模型中的甲状腺功能、促甲状腺激素受体抗体和眼眶粘蛋白/胶原蛋白含量

背景

接受表达促甲状腺素受体 A 亚基 (TSHR) 的腺病毒 (Ad) 长期免疫接种的 BALB/c 小鼠发展为稳定的格雷夫斯病 (GD)。TSHR 衍生的环肽 19 (P19) 在该模型中被确定为有效的治疗方法。

方法

在 Ad-TSHR 小鼠中，我们通过在独立实验室中使用新的检测方法研究了长达 4 个月的更短的疾病间隔，以了解眼眶的组织学改变、抗TSHR 抗体 (Ab) 和游离甲状腺素 (fT4) 激素水平的微调。在第四次 Ad-TSHR 免疫后（第 11 周）静脉内给予治疗（0.3 mg/kg P19 或载体）并持续到第 19 周。

结果

促甲状腺激素结合抑制性免疫球蛋白（TBII，桥式免疫测定）、阻断（TBAb）和刺激（TSAb）TSHR-Ab（两种基于细胞的生物测定）和血清 fT4 水平在第 11 周时在 Ad-TSHR 免疫小鼠中显着升高，而没有在对照小鼠中。首次在第 21 周分别在 19、12/19 和 6/19 Ad-TSHR 免疫小鼠中的 17 只中检测到 TSAb、TBAb 和甲状腺过氧化物酶-Ab。此外，本研究首次表明 P19治疗显着降低了 Ad-TSHR 免疫小鼠眼眶组织中的血清 TBII (p < 0.0001)、血清 fT4 (p = 0.02) 和酸性粘蛋白和胶原蛋白含量。

结论

P19 显着改善了甲状腺功能，证实了之前在独立第二实验室的结果。响应 P19 治疗的抗TSHR 抗体亚群的相关转变可能有助于解释其免疫学效应。此外，P19 对眼眶组织的粘蛋白和胶原蛋白含量产生有益的影响。因此，P19 为 GD 和相关眼眶病提供了一种潜在的新治疗方法。