| 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)
田村 敏生 東京大学, 医科学研究所, 助手 (40291306)
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| Budget Amount *help |
¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 1999: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1998: ¥4,700,000 (Direct Cost: ¥4,700,000)
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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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