Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunity.
Induction of antigen-specific Treg cells in treating autoimmune uveitis via bystander suppressive pathways without compromising anti-tumor immunity.
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DOI：
10.1016/j.ebiom.2021.103496
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发表时间：
2021-08
期刊：
影响因子：
11.1
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Chen Z;Zhang T;Kam HT;Qiao D;Jin W;Zhong Y;Zhou M;Zhou H;Chong WP;Chen W;Chen J
诱导自身抗原特异性Treg细胞在不影响有益免疫反应的情况下抑制组织特异性自身免疫是自身免疫性疾病免疫治疗的圣杯。在模拟人葡萄膜炎的实验性自身免疫性葡萄膜炎(EAU)模型中，用视网膜抗原光感受器间视黄醇结合蛋白(IRBP)免疫诱导眼部炎症。小鼠发病后给予α抗体(Ab)腹腔注射，随后给予IRBP。对EAU进行临床和功能评价。分离脾细胞、CD_4+CD_(25)−和CD_4+CD_(25+)T细胞，分别与IRBP或αCD_3单抗共同培养。检测T细胞增殖和细胞因子的产生。该实验方法缓解了EAU小鼠的眼部炎症，并挽救了其视觉功能。从机制上讲，这种治疗作用是通过诱导抗原特异性Treg细胞以转化生长因子-β和IL-10依赖的方式抑制IRBP驱动的Th17反应而实现的。重要的是，抗体介导的免疫耐受可以通过注射视网膜自身抗原，Arrestin，但不限于IRBP，以抗原非特异性旁观者的方式在EAU小鼠中实现。此外，这些EAU抑制耐受的小鼠在黑色素瘤模型中并没有损害它们的抗肿瘤T免疫。我们通过在体内诱导自身抗原特异性Treg细胞而不损害宿主整体T细胞免疫，成功地解决了EAU的特异性免疫治疗，这应该对自身免疫性葡萄膜炎患者具有潜在的意义。本研究得到广东省自然科学基金和中山眼科中心眼科国家重点实验室基础研究基金的资助。
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, CD4+CD25− and CD4+CD25+ 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.
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影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
32.4
作者：
Chen, WJ;Frank, ME;Wahl, SM
通讯作者：
Wahl, SM
影响因子：
12.8
作者：
CHAN, CC;CASPI, RR;NUSSENBLATT, RB
通讯作者：
NUSSENBLATT, RB
影响因子：
2
作者：
CASPI, RR;CHAN, CC;CHADER, GJ
通讯作者：
CHADER, GJ
DOI：
10.1007/978-1-60761-720-4_22
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Agarwal, Rajeev K;Silver, Phyllis B;Caspi, Rachel R
通讯作者：
Caspi, Rachel R