Co-Investigator(Kenkyū-buntansha) |
NAKANO Hideki Toho University, School of Medicine, Research Associate, 医学部, 助手 (30266928)
YOSHIMOTO Takayuki University of Tokyo, Institute of Medical Science, Research Associate, 医科学研究所, 助手 (80202406)
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Research Abstract |
Using MRL/MpJ-lprィイD1cgィエD1/lprィイD1cgィエD1 (lprィイD1cgィエD1) mice, we produced lprィイD1cgィエD1 mice carrying Vβ8.2-reactive viral superantigen (vSAG+lprィイD1cgィエD1), those deficient in the membrane-bound CD4 molecule by introducing a mutant gene (CD4-lprィイD1cgィエD1), those transgenic for the IL-12p40 gene (p4D+lprィイD1cgィエD1), and those targeted for IL-1α/β genes (IL-1-lprィイD1cgィエD1) to investigate the roles or T cells and cytokines in the development of autoimmune manifestations. In vSAG+lprィイD1cgィエD1 and CD4-lprィイD1cgィエD1 mice, the clinical symptoms including proteinuria and glomerulonephritis were clearly improved and lymphadenopathy was ameliorated. Immunoglobulin, autoreactive factors such as immune complexes (IC), antinuclear antibodies and anti-DNA antibodies, and INF-γ were generally decreased in the blood. The glomerular IC deposition in the kidney and the content or B220ィイD1+ィエD1CD4ィイD1-ィエD1CD8T cells in lymph nodes were markedly reduced. The results indicate that Vβ8.2+CD4+T cells p
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lay a crucial role in the development or autoimmune diseases and that their depletion leads to the reduced glomerulonephritis resulting from the suppressed production of autoreactive factors. In p40+lprィイD1cgィエD1 mice, the blood p40 level were several thousand times higher, the level or a representative autoantibody, anti-DNA, decreased in the IgG2a but rather increased in the IgG1 subclass, and the production or INF-γ was suppressed compared to wild-type lprィイD1cgィエD1 mice, suggesting that p40 might suppress the functions of Th1 cells through its inhibitory activity against IL-12. Although proteinuria and survival were slightly improved, the effects on IC production, lymphadenopathy, glomerulonephritis and vasculitis were minimal or insignificant. In IL-1-lprィイD1cgィエD1 mice, the clinical manifestations were not improved at all, and unexpectedly, lymphoproliferation was markedly enhanced. Based on these results, we have concluded that the gene therapies targeting T cells are more effective than those targeting cytokines. Less
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