Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, and Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA; email:
Annu Rev Pharmacol Toxicol. 2019 Jan 6;59:129-148. doi: 10.1146/annurev-pharmtox-010617-052509. Epub 2018 Jul 25.
Thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves' disease, is a process in which orbital connective tissues and extraocular muscles undergo inflammation and remodeling. The condition seems to result from autoimmune responses to antigens shared by the thyroid and orbit. The thyrotropin receptor (TSHR), expressed at low levels in orbital tissues, is a leading candidate antigen. Recent evidence suggests that another protein, the insulin-like growth factor-I receptor (IGF-IR), is overexpressed in TAO, and antibodies against IGF-IR have been detected in patients with the disease. Furthermore, TSHR and IGF-IR form a physical and functional complex, and signaling initiated at TSHR requires IGF-IR activity. Identification of therapy for this rare disease has proven challenging and currently relies on nonspecific and inadequate agents, thus representing an important unmet need. A recently completed therapeutic trial suggests that inhibiting IGF-IR activity with a monoclonal antibody may be an effective and safe treatment for active TAO.
甲状腺相关眼病（TAO）是格雷夫斯病的眼部表现，是眶内结缔组织和眼外肌发生炎症和重塑的过程。这种情况似乎是由于针对甲状腺和眼眶共有的抗原的自身免疫反应引起的。促甲状腺激素受体（TSHR）在眼眶组织中低表达，是主要的候选抗原。最近的证据表明，另一种蛋白质，胰岛素样生长因子-I 受体（IGF-IR）在 TAO 中过度表达，并且在患有该疾病的患者中检测到针对 IGF-IR 的抗体。此外，TSHR 和 IGF-IR 形成物理和功能复合物，并且在 TSHR 处起始的信号传导需要 IGF-IR 活性。证明针对这种罕见疾病的治疗具有挑战性，目前依赖于非特异性和不充分的药物，因此代表了一个重要的未满足的需求。最近完成的一项治疗试验表明，用单克隆抗体抑制 IGF-IR 活性可能是治疗活动性 TAO 的有效且安全的治疗方法。
