Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan.
Br J Ophthalmol. 2010 Jun;94(6):802-7. doi: 10.1136/bjo.2009.171314. Epub 2009 Dec 3.
To determine whether an active metabolite of vitamin A, all-trans retinoic acid (ATRA), reduces inflammation in experimental autoimmune uveoretinitis (EAU).
Naive CD4(+) T cells were activated with anti-CD3, anti-CD28 and transforming growth factor (TGF)-beta, in the presence or absence of ATRA. Intracellular expression of transcription factor forkhead box P3 (Foxp3) and interleukin (IL)-17 in the activated CD4(+) T cells was assessed by flow cytometry. C57BL/6 mice were immunised with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP(1-20)). ATRA was administered intraperitoneally every other day (0.2 mg/mouse per day) from day 0 to day 21. In vivo-primed draining lymph node cells from vehicle-treated or ATRA-treated mice were stimulated with IRBP(1-20) and the culture supernatant fraction was harvested for assay of interferon (IFN)-gamma and IL-17 by ELISA.
ATRA synergised with TGF-beta to induce Foxp3(+) T regulatory cells (Treg) and reciprocally inhibited development of IL-17-producing T helper cells (Th17) induced by TGF-beta and IL-6. ATRA treatment reduced the severity of EAU clinically, and IFN-gamma and IL-17 production were significantly reduced in ATRA-treated mice.
These findings demonstrate that ATRA treatment ameliorates severity of EAU and reduces the Th1/Th17 responses. ATRA may represent a new therapeutic modality for human refractory uveitis.
确定维生素 A 的活性代谢产物全反式视黄酸 (ATRA) 是否能减轻实验性自身免疫性葡萄膜炎 (EAU) 中的炎症。
在存在或不存在 ATRA 的情况下，用抗 CD3、抗 CD28 和转化生长因子 (TGF)-β激活幼稚 CD4(+) T 细胞。通过流式细胞术评估激活的 CD4(+) T 细胞中转录因子叉头框 P3 (Foxp3) 和白细胞介素 (IL)-17 的细胞内表达。用人眼间感光细胞视黄醇结合蛋白肽 1-20 (IRBP(1-20)) 免疫 C57BL/6 小鼠。从第 0 天到第 21 天，每天每只腹腔内给予 ATRA0.2mg/mouse。用 IRBP(1-20) 刺激 vehicle 处理或 ATRA 处理小鼠的体内预致敏引流淋巴结细胞，并收获培养上清液进行 IFN-γ和 IL-17 的 ELISA 测定。
ATRA 与 TGF-β协同诱导 Foxp3(+)T 调节细胞 (Treg)，并反向抑制 TGF-β和 IL-6 诱导的 IL-17 产生的 Th17 细胞的发育。ATRA 治疗可减轻 EAU 的严重程度，并且 ATRA 治疗小鼠的 IFN-γ和 IL-17 产生显著减少。
这些发现表明 ATRA 治疗可改善 EAU 的严重程度，并减少 Th1/Th17 反应。ATRA 可能代表人类难治性葡萄膜炎的一种新的治疗方式。
