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

通过调节巨噬细胞功能来抑制小鼠实验性自身免疫性葡萄膜视网膜炎的模型的开发

基本信息

批准号：
13671814
负责人：
IWABUCHI Kazuya
金额：
$ 2.3万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671814/
关键词：
MACROPHAGE UVEORETINITIS MCP-1 TRANSGENIC MOUSE MONOCLONAL ANTIBODY BEHCET'S DISEASE EXPERIMENTAL THERAPEUTICS

项目摘要

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

我们已经建立了3系在全身（包括血清）表达人单核细胞趋化蛋白-1（hMCP-1）的转基因小鼠（Tgm）。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处理时，获得更高的组织病理学评分。结果与以下发现一致：与用对照抗体处理的小鼠相比，用中和性抗hMCP-1抗体处理的小鼠的增殖反应和细胞因子（例如TNF-α、IFN-γ和IL-5）产生更高。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