Procorde, Advancecor, Fraunhoferstrasse 9a, 82152 Martinsried, Germany,
Procorde, Advancecor, Fraunhoferstrasse 9a, 82152 Martinsried, Germany.
Front Biosci (Landmark Ed). 2018 Jun 1;23(11):2044-2052. doi: 10.2741/4688.
Graves´ disease is an autoimmune disorder, which is characterized by stimulatory antibodies targeting the human thyrotropin receptor (TSHR), resulting in hyperthyroidism and multiple organ damage. The disease can be modelled in mice using adenoviral immunizations with the extracellular A subunit of the TSHR, which induces a long-term stable disease state. TSHR binding cAMP-stimulatory antibodies, thyroid enlargement, elevated serum thyroxin levels, tachycardia, cardiac hypertrophy and orbitopathy are observed in these Ad-TSHR-immunized mice. T cell epitope-derived linear peptides have been identified using immunized HLA-DR3 transgenic mice, which may induce tolerance towards TSHR. A combination of such peptides are being investigated in a first clinical phase I trial in patients with Graves´ disease. Alternatively, intravenous administration of cyclic peptides derived from the interaction site of the TSHR A domain with stimulatory anti-TSHR antibodies can re-establish tolerance towards the antigen in immunized mice, improving symptoms of Graves´ disease within 3 - 4 months after starting these therapies. In immunologically naïve mice, administration of the cyclic peptides did not induce any immune response.
格雷夫斯病是一种自身免疫性疾病，其特征是针对人类促甲状腺激素受体（TSHR）的刺激抗体，导致甲状腺功能亢进和多器官损伤。可以使用腺病毒免疫 TSHR 的细胞外 A 亚单位在小鼠中模拟这种疾病，这会诱导长期稳定的疾病状态。在这些 Ad-TSHR 免疫的小鼠中，观察到 TSHR 结合 cAMP 刺激抗体、甲状腺肿大、血清甲状腺素水平升高、心动过速、心脏肥大和眼病。使用免疫 HLA-DR3 转基因小鼠鉴定了 T 细胞表位衍生的线性肽，这些肽可能诱导对 TSHR 的耐受。正在对 Graves 病患者进行的首次临床 I 期试验中研究了此类肽的组合。或者，静脉内给予源自 TSHR A 结构域与刺激性抗 TSHR 抗体相互作用位点的环状肽可以在免疫小鼠中重新建立对抗原的耐受，在开始这些治疗后 3-4 个月内改善 Graves 病的症状。在免疫原性未成熟的小鼠中，给予环状肽不会引起任何免疫反应。
