Prevention of experimental autoimmune uveoretinitis by vasoactive intestinal peptide
Prevention of experimental autoimmune uveoretinitis by vasoactive intestinal peptide
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DOI：
10.1001/archopht.122.8.1179
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发表时间：
2004-08-01
影响因子：
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通讯作者：
Usui, M
中科院分区：
文献类型：
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作者：
Keino, HO;Kezuka, T;Usui, M
背景：血管活性肠肽（VIP）是一种存在于淋巴组织微环境中的神经肽，具有显著的抗炎作用。目的：探讨VIP在实验性自身免疫性葡萄膜视网膜炎（EAU）发展中的潜在作用。设计：我们用人光感受器间类维甲酸结合蛋白肽1-20 （h-IRBP肽）免疫C57BL/6小鼠。免疫后隔天腹腔注射血管活性肠肽，直至免疫后第21天（全组）。在某些情况下，在h-IRBP肽诱导免疫后的不同时间点注射VIP（传出组）。在每个实验中，对照组小鼠注射磷酸盐缓冲盐水代替VIP。免疫后第21天通过组织学检查评价EAU的发展情况。此外，我们确定静脉注射用VIP培养的腹膜渗出细胞是否能在体外过夜消除EAU。我们分析了迟发性h-IRBP肽超敏反应和EAU的发生和严重程度，通过评估炎性眼部疾病的组织病理学切片。结果：VIP治疗可显著抑制h-IRBP肽延迟性超敏反应的表达（阳性对照组与对照组相比，P = 0.02，阳性对照组与传出组相比，P < 0.001）。组织病理学分析显示，与未治疗小鼠（发生率80%，平均评分0.85，中位评分0.75）相比，VIP治疗小鼠（n = 10）的EAU发生率（40%）和严重程度（全组平均评分0.3，中位评分0）降低（P = 0.049）。即使在免疫后第8 ~ 20天给予VIP，也观察到VIP对EAU的抑制作用（输出组[n = 9]发生率为11%，平均评分为0.1，中位数评分为0）（P = 0.003）。此外，与VIP治疗组（平均评分0.3，中位数评分0，发生率30% [n = 10]）相比，在VIP存在下用h-IRBP脉冲的腹膜渗出细胞预处理动物（对照平均评分1.2，中位数评分1.0，发生率80% [n = 10]）， EAU的表达明显受到抑制（P = 0.004）。此外，与vip治疗组（平均评分0.08，中位数评分0，发生率17% [n = 6]）相比，vip治疗组（平均评分0.08，中位数评分0，发生率17% [n = 6]）， vip处理的腹膜渗出细胞在受体小鼠脾脏中产生能够干扰EAU发展的调节性T细胞（对照组平均评分0.5，中位数评分0.5，发生率63% [n = 8]） （P = .08）。结论：VIP治疗是抑制EAU的有效方法。临床意义：由于其预防EAU的有效性，VIP可能被认为是治疗人类葡萄膜炎的一种新的治疗方式。
Background: Vasoactive intestinal peptide (VIP), a neuropeptide that is known to be present in lymphoid tissue microenvironments, shows prominent anti-inflammatory actions.Objective: To examine the potential effect of VIP on the development of experimental autoimmune uveoretinitis (EAU).Design: We immunized C57BL/6 mice with human interphotoreceptor retinoid-binding protein peptide 1-20 (h-IRBP peptide). Vasoactive intestinal peptide was administered intraperitoneally on alternate days until day 21 after immunization (entire group). In some cases, VIP was injected at different time points after the induction of immunity with h-IRBP peptide (efferent group). In each experiment, a control group of mice was injected with phosphate-buffered saline instead of VIP. Development of EAU was evaluated by means of histological examination on day 21 after immunization. Furthermore, we determined whether intravenous injection of peritoneal exudate cells cultured with VIP overnight in vitro abrogated EAU. We analyzed delayed hypersensitivity for h-IRBP peptide and the occurrence and severity of EAU using evaluation of histopathological sections for inflammatory ocular disease. IResults: Treatment with VIP suppressed the expression of delayed hypersensitivity responses to h-IRBP peptide significantly (positive control vs entire group, P = .02 positive control vs efferent group, P < .001). Mice treated with VIP (n = 10) showed a lower occurrence (40%) and decreased severity of EAU (entire group mean score, 0.3; median score, 0) compared with untreated mice (occurrence, 80%; mean score, 0.85; median score, 0.75), as assessed by histopathological analyses (P = .049). Suppressive effects of VIP on EAU were also observed, even when VIP was administered on days 8 through 20 after immunization (efferent group [n = 9] occurrence, 11%; mean score, 0.1; median score, 0) (P = .003). Moreover, expression of EAU was significantly suppressed when the animals were pretreated with peritoneal exudate cells pulsed with h-IRBP in the presence of VIP (control mean score, 1.2; median score, 1.0; occurrence, 80% [n = 10]) compared with the VIP-treatment group (mean score, 0.3; median score, 0; occurrence, 30% [n = 10]) (P = .004). In addition, VIP-treated peritoneal exudate cells generated regulator T cells in the spleens of recipient mice that were able to interfere with the development of EAU (control group mean score, 0.5; median score, 0.5; occurrence, 63% [n = 8]) compared with the VIP-treatment group (mean score, 0.08; median score, 0; occurrence, 17% [n = 6]) (P = .08).Conclusion: Treatment with VIP is a highly effective therapy to suppress EAU.Clinical Relevance: As a result of its efficacy in preventing EAU, VIP might be considered as a novel therapeutic modality for human uveitis.