Erasmus Medical Center, Department of Internal Medicine, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Cells. 2021 Feb 12;10(2):383. doi: 10.3390/cells10020383.
Complex immunological mechanisms underlie the pathogenesis of thyroid-associated ophthalmopathy (TAO). Historical models of Graves' disease and TAO have focused almost entirely on autoimmune reactivity directed against the thyrotropin receptor (TSHR). The insulin-like growth factor-I receptor (IGF-IR) has been proposed as a second participating antigen in TAO by virtue of its interactions with IGFs and anti-IGF-IR antibodies generated in Graves' disease. Furthermore, the IGF-IR forms with TSHR a physical and functional complex which is involved in signaling downstream from both receptors. Inhibition of IGF-IR activity results in attenuation of signaling initiated at either receptor. Based on the aggregate of findings implicating IGF-IR in TAO, the receptor has become an attractive therapeutic target. Recently, teprotumumab, a human monoclonal antibody IGF-IR inhibitor was evaluated in two clinical trials of patients with moderate to severe, active TAO. Those studies revealed that teprotumumab was safe and highly effective in reducing disease activity and severity. Targeting IGF-IR with specific biologic agents may result in a paradigm shift in the therapy of TAO.
甲状腺相关性眼病（TAO）的发病机制涉及复杂的免疫机制。既往 Graves 病和 TAO 的模型几乎完全集中于针对促甲状腺激素受体（TSHR）的自身免疫反应。由于胰岛素样生长因子-I 受体（IGF-IR）与 IGFs 相互作用，并在 Graves 病中产生抗 IGF-IR 抗体，因此被认为是 TAO 中的第二个参与抗原。此外，IGF-IR 与 TSHR 形成物理和功能复合物，参与两个受体下游的信号转导。抑制 IGF-IR 活性可减弱两个受体起始的信号转导。基于 IGF-IR 参与 TAO 的综合研究结果，该受体已成为有吸引力的治疗靶点。最近，人源化单克隆抗体 IGF-IR 抑制剂 teprotumumab 在两项中度至重度、活动性 TAO 患者的临床试验中进行了评估。这些研究表明，teprotumumab 安全且能高度有效地降低疾病活动度和严重程度。用特异性生物制剂靶向 IGF-IR 可能会使 TAO 的治疗发生范式转变。
