State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060 China.
Mucosal Immunology Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
EBioMedicine. 2021 Aug;70:103496. doi: 10.1016/j.ebiom.2021.103496. Epub 2021 Jul 16.
Induction of autoantigen-specific Treg cells that suppress tissue-specific autoimmunity without compromising beneficial immune responses is the holy-grail for immunotherapy to autoimmune diseases.
In a model of experimental autoimmune uveitis (EAU) that mimics human uveitis, ocular inflammation was induced by immunization with retinal antigen interphotoreceptor retinoid-binding protein (IRBP). Mice were given intraperitoneal injection of αCD4 antibody (Ab) after the onset of disease, followed by administration of IRBP. EAU was evaluated clinically and functionally. Splenocytes, CD4CD25 and CD4CD25 T cells were sorted and cultured with IRBP or αCD3 Ab. T cell proliferation and cytokine production were assessed.
The experimental approach resulted in remission of ocular inflammation and rescue of visual function in mice with established EAU. Mechanistically, the therapeutic effect was mediated by induction of antigen-specific Treg cells that inhibited IRBP-driven Th17 response in TGF-β and IL-10 dependent fashion. Importantly, the Ab-mediated immune tolerance could be achieved in EAU mice by administration of retinal autoantigens, arrestin but not limited to IRBP only, in an antigen-nonspecific bystander manner. Further, these EAU-suppressed tolerized mice did not compromise their anti-tumor T immunity in melanoma model.
We successfully addressed a specific immunotherapy of EAU by in vivo induction of autoantigen-specific Treg cells without compromising host overall T cell immunity, which should have potential implication for patients with autoimmune uveitis.
This study was supported by the Natural Science Foundation of Guangdong Province and the Fundamental Research Fund of the State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center.
诱导能够特异性抑制组织自身免疫而不影响有益免疫反应的自身抗原特异性调节性 T 细胞是自身免疫性疾病免疫治疗的圣杯。
在模拟人类葡萄膜炎的实验性自身免疫性葡萄膜炎（EAU）模型中，通过用视网膜抗原间视觉感受器视黄醇结合蛋白（IRBP）免疫诱导眼部炎症。疾病发作后，给小鼠腹腔内注射 αCD4 抗体（Ab），然后给予 IRBP。临床和功能评估 EAU。分离和培养脾细胞、CD4CD25 和 CD4CD25 T 细胞，并用 IRBP 或 αCD3 Ab 处理。评估 T 细胞增殖和细胞因子产生。
该实验方法导致已建立的 EAU 小鼠眼部炎症缓解和视觉功能恢复。从机制上讲，治疗效果是通过诱导抗原特异性 Treg 细胞介导的，这些细胞以 TGF-β和 IL-10 依赖的方式抑制 IRBP 驱动的 Th17 反应。重要的是，通过以抗原非特异性旁观者方式施用视网膜自身抗原，即 arrestin 而不仅限于 IRBP，在 EAU 小鼠中可以实现 Ab 介导的免疫耐受。此外，这些抑制 EAU 的耐受小鼠在黑色素瘤模型中并未损害其抗肿瘤 T 免疫。
我们通过体内诱导自身抗原特异性 Treg 细胞成功解决了 EAU 的特定免疫治疗问题，而不影响宿主整体 T 细胞免疫，这对于自身免疫性葡萄膜炎患者应该具有潜在意义。
本研究得到广东省自然科学基金和中山大学中山眼科中心眼科学国家重点实验室基础研究基金的支持。
