DEVELOPMENT OF A MODEL FOR SUPPRESSING EXPERI-MENTAL AUTOIMMUNE UVEORETINITIS IN MICE THROUGH AN MODULATION OF MACROPHAGE FUNCTIONS

我们建立了3个转基因小鼠品系，在包括血清在内的全身表达人单核细胞趋化蛋白-1（hMCP-1）。两个品系在血清中产生非常高水平的hMCP-1（> 10 ng/ml），而一个品系略低于其他品系（5-6 ng/ml）。为了检查葡萄膜炎的发展是否受到干扰MCP-1作用的影响或阻断，我们分析了在中和抗体存在下产生较高hMCP-1或C57 BL/6（B6）小鼠的hMCP-1 Tgm中的实验性自身免疫性葡萄膜视网膜炎（EAU（Ab ; 2 H5）对hMCP-1的诱导作用。EAU通过皮下注射乳化的感光细胞间维甲酸结合蛋白p1-完全弗氏佐剂和腹腔注射百日咳毒素。按Thurau标准（0-4）进行临床评分。每天以5μg/小鼠施用中和抗体和对照抗体，持续3周。所有程序符合北海道大学委员会的规定， ...更多信息 与非Tgm相比，Tgm发展为严重的葡萄膜炎或相同严重程度的葡萄膜炎，但发病较早。当用IRBP p1-20致敏的C57 BL/6小鼠用中和性抗Hmcp-1 Ab治疗时，获得了更高的组织病理学评分。该结果与以下发现一致，即在用中和性抗hMCP-1 Ab处理的小鼠中证实了比用对照Ab处理的小鼠更高的增殖应答和细胞因子产生，如TNF-α、IFN-γ和IL-5。后者的结果表明，从EAU诱导的早期阶段开始的抗MCP-1的中和相当加重但不改善疾病。结论：（1）MCP-1参与EAU的发病过程;（2）MCP-1的中和作用可能导致EAU的加重而非缓解，其作用机制取决于作用时间。少

We have established 3 lines of transgenic mice (Tgm) that express human monocyte chemoattractant protein-1 (hMCP-1) in whole body including serum. Two lines produce very high level of hMCP-1 in sera (> 10 ng/ml), while one line slightly lower than the others (5-6 ng/ml). To examine whether a development of uveitis is either affected or blocked by interfering MCP-1 actions, we analyzed experimental autoimmune uveoretinitis (EAU) in hMCP-1 Tgm that produce higher hMCP-1 or C57BL/6 (B6) mice in the presence of a neutralizing antibody (Ab ; 2H5) to hMCP-1.EAU was induced by immunizing subcutaneous injection of emulsified interphotoreceptor retinoid-binding protein p1-20 with complete Freund's adjuvant and intraperitoneal injection of pertussis toxin. A clinical score was evaluated accordong to Thurau's standard (0-4). Neutralizing and control antibodies were administered everyday for 3 wk at 5μg/mouse. All procedures conformed to the regulations of Hokkaido University Committee for the ani … More mal experimentation.Tgm developed either severe uveitis or uveitis of the same severity with an earlier onset in comparison with non-Tgm. When C57BL/6 mice sensitized with IRBP p1-20 were treated with neutralizing anti-Hmcp-1 Ab, higher histopathological scores were obtained. The result was consistent with the findings that higher proliferative responses and cytokine productions, such as TNF-α, IFN-γ, and IL-5, were demonstrated in mice treated with a neutralizing anti-hMCP-1 Ab than in mice treated with control Ab. The latter results indicate that the neutralization of anti-MCP-1 from the early phase of induction of EAU rather excerbates but not ameliorate the disease. Although mechanisms of the each phenomenon is still elusive, an overproduction of TNF-α both in hMCP-1 Tgm and B6 mice treated with anti-hMCP-1 Ab may in part explain the rather contradictory results.Conclusion :1) MCP-1 is involved in the pathogenesis of EAU.2) Neutralization of MCP-1 may cause excerbation rather than amelioration depending on the application period. Less