Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-κB (NF-κB), pyrrolidine dithiocarbamate
Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-κB (NF-κB), pyrrolidine dithiocarbamate
复制标题
DOI：
10.1189/jlb.0805453
复制
发表时间：
2006-06-01
影响因子：
5.5
通讯作者：
Onoe, Kazunori
中科院分区：
文献类型：
--
作者：
Kitamei, Hirokuni;Iwabuchi, Kazuya;Onoe, Kazunori
实验性自身免疫性葡萄膜视网膜炎（Experimental autoimmune uveoretinitis，EAU）是一种由I型T辅助细胞介导的自身免疫性疾病，可作为人类慢性葡萄膜炎的模型。在该模型中，单核细胞/巨噬细胞谱系的细胞和视网膜抗原（Ag）特异性T细胞浸润到视网膜中并引起炎性病变，其中促炎细胞因子和各种刺激物激活转录因子核因子-κ B（NF-κ B），其调节炎症并增强免疫应答。在本研究中，在小鼠EAU模型中检查了NF-κ B抑制剂吡咯烷二硫代氨基甲酸酯（PDTC）给药的治疗效果。结果表明，PDTC可改善EAU小鼠的临床症状，并显著降低组织病理学评分。PDTC处理的EAU汁抑制了眼内肿瘤坏死因子α和白细胞介素-1 β的mRNA表达。然而，当PDTC处理的EAU小鼠，Ag呈递细胞（APC），和视网膜Ag肽的T细胞共培养，这些T细胞表现出相同的增殖水平，从对照小鼠。此外，在EAU小鼠T细胞培养物中添加PDTC、Ag和APC完全消除了T细胞增殖反应和细胞因子产生。在体外用PDTC预处理Ag致敏的T细胞或APC也降低了这些反应。这些结果表明，PDTC的抑制作用主要归因于抑制效应相反应，包括炎症，而不是抑制T细胞启动。调节病变中的NF-κ B途径可能是成功控制葡萄膜视网膜炎的新靶点。
Experimental autoimmune uveoretinitis (EAU) is a T helper type I cell-mediated autoimmune disease, which serves as a model of human chronic uveitis. In this model, cells of a monocyte/ macrophage lineage and retinal antigen (Ag)-specific T cells infiltrate into the retina and cause inflammatory lesion, where proinflammatory cytokines and various stimuli activate a transcriptional factor, nuclear factor-kappa B (NF-kappa B), which modulates inflammation and enhances immune responses. In the present study, the therapeutic effect of administration of a NF-kappa B inhibitor, pyrrolidine dithiocarbamate (PDTC), was examined in a murine EAU model. It was shown that PDTC ameliorated the clinical symptoms of EAU mice and significantly reduced the histopathological score compared with those in untreated mice. mRNA expressions of tumor necrosis factor alpha and interleukin-1 beta were suppressed in eyes of PDTC-treated EAU juice. However, when T cells from PDTC-treated EAU mice, Ag-presenting cells (APC), and the retinal Ag peptides were cocultured, these T cells showed the same level of proliferation as those from control mice. Furthermore, addition of PDTC in the culture of T cells from EAU mice, Ag, and APC completely abrogated the T cell-proliferative response and cytokine production. Pretreatment of Ag-primed T cells or APC with PDTC in vitro also reduced these responses. These results indicate that the inhibitory effect of PDTC is attributed mainly to the suppression of effector-phase responses including inflammation but not to the inhibition of T cell priming. Regulation of NF-kappa B pathway in the lesion could be a novel target for the successful control of uveoretinitis.