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

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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