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Elucidation of the mechanism how Vβ T cells aggravate autoimmune diseases and establishment of T cell receptor (TCR)-targeted gene therapies of autoimmune diseases

阐明Vβ T细胞加重自身免疫性疾病的机制并建立针对自身免疫性疾病的T细胞受体（TCR）靶向基因治疗

基本信息

批准号：
10470055
负责人：
TAMURA Toshiki
金额：
$ 4.67万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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 … More 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

利用mRL/mpJ-lprィイD1cgィエD1/lprィイD1cgィエD1(lprィイD1cgィエD1)小鼠，获得携带VCD48.2反应性病毒超抗原(vSAG+lprィイD1cgィエD1)的lpRβD1cgィイD1，通过引入突变基因(ィエ-lprィイD1cgィエd1)获得膜结合CD4分子缺陷的小鼠，转IL-12p40基因的小鼠(P4D+lprィイD1cgィエd1)，并以IL-1α/β基因(IL-1-lprィイD1cgィエD1)为靶点，探讨T细胞和细胞因子在自身免疫表现发展中的作用。VSAG+lprィイD1cgィエd1和CD4-lprィイD1cgィエd1小鼠的蛋白尿、肾小球肾炎等临床症状明显改善，淋巴组织病变明显改善。免疫球蛋白、自身反应因子如免疫复合体、抗核抗体和抗脱氧核糖核酸抗体以及干扰素-γ在血液中普遍降低。肾小球内IC沉积和淋巴结中B220ィイD1+ィエD1CD4、ィイD1-ィエD1CD8T细胞数量明显减少。结果表明，Vβ8.2+CD4+T细胞p…More在自身免疫性疾病的发展中起着至关重要的作用，它们的耗尽会导致自身反应因子的抑制而导致肾小球肾炎的减轻。P40+lprィイD1cgィエD1小鼠的血液p40水平比野生型lprγD1cgィイD1小鼠高几千倍，IgG2a抗体水平下降，而IgG1亚类抗体水平升高，干扰素-ィエ的产生受到抑制，提示p40可能通过抑制IL-12而抑制Th1细胞的功能。虽然蛋白尿和存活率略有改善，但对IC产生、淋巴结病、肾小球肾炎和血管炎的影响很小或不显著。IL-1-lprィイD1cgィエD1小鼠的临床表现丝毫没有改善，而且淋巴细胞增殖明显增强。根据这些结果，我们得出结论，靶向T细胞的基因治疗比靶向细胞因子的基因治疗更有效。较少