Amelioration of lpr^<cg>-induced autoimmune diseases with Vbeta8.2-specific viral superantigen and its application to gene therapy in mice

Vbeta8.2特异性病毒超抗原改善lpr^<cg>诱导的自身免疫性疾病及其在小鼠基因治疗中的应用

• 批准号: 08457069
• 负责人: MATSUZAWA Akio
• 金额: $ 4.8万
• 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: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457069/
• 关键词: Autoimmune disease; Superantigen; lpr^<cg> gene; Mammary tumor virus; Vbeta8.2+ T cells; MRL mice; Lymphoproliferation; Gene therapy; 1pr^<cg>遺伝子

MRL-lpr^<cg>/lpr^<cg> (MRL-lpr^<cg>) mice were established by introducing lpr^<cg> gene into MRL mice by 12 generations of backcross. Their newborns were forster-nursed on FM mothers to establish MRL-lpr^<cg>fFM carrying mouse mammary tumor virus (MMTV) encoding Vbeta8.2-specific superantigen (SAg). One-year survey revealed that MRL-lpr^<cg>fFM mice survived longer and had lower levels of proteinuria than MRL-lpr^<cg>. Autopsy at 3 and 5 months of age demonstrated less severe lymphoproliferative disease in MRL-lpr^<cg>fFM.Histological and immunofluorescent examinations indicated that the incidence of clinical glomerulonephritis was clearly lower and the amount of adhered immune complex was smaller in MRL-lpr^<cg>fFM than in MRL-lpr^<cg> mice. Serological analyzes revealed that the total IgG level and anti-DNA antibody levels of IgG class and IgG2a and IgG3 subclasses were lower in MRL-lpr^<cg>fFM mice. Vbeta8.2+ cells were almost completely depleted in CD4+, CD8+ and CD4-8- T cell populations in MRL-lpr^<cg>fFM mice. These results evidenced that MMTV (FM) SAg ameliorated autoimmune diseases by suppressing autoantibody production through deletion of Vbeta8.2+ cells and support the application of viral SAg to gene therapy.

将LPR^&lt；Cg&gt；/LPR^&lt；Cg&gt；(MRL-LPR^&lt；Cg&gt；)基因导入MRL-LPR^&lt；Cg&gt；(MRL-LPR^&lt；Cg&gt；)小鼠，经12代回交获得MRL-LPR^&lt；Cg&gt；小鼠。他们的新生儿在FM母亲的哺育下建立了携带编码Vbeta8.2特异性超抗原(SAG)的小鼠乳腺肿瘤病毒(MMTV)的MRL-LPR&lt；CG&GT；FFM。一年的调查显示，MRL-LPR；&lt；CG&gt；FFM小鼠比MRL-LPR；&lt；CG&gt；FFM小鼠存活时间更长，蛋白尿水平更低。3月龄和5月龄尸检显示，MRL-LPR；cg&gt；fFM的淋巴组织增殖性疾病较轻。组织学和免疫荧光检查显示，mRL-lpr；lt；cg&gt；fFM的临床肾小球肾炎发生率明显低于mrl-lpr；lt；cg&gt；fFM小鼠，黏附免疫复合体的数量明显少于mrl-lpr；lt；cg&gt；fFM。血清学分析表明，MRL-LPR^&lt；CG&GT；FFM小鼠的总免疫球蛋白水平和抗DNA抗体水平较低，IgG2a和IgG3亚类抗体水平较低。在MRL-LPR；CG&GT；FFM小鼠中，CD4+、CD8+和CD4-8-T细胞群中的Vbeta8.2+细胞几乎完全耗尽。这些结果表明，MMTV(FM)SAG通过缺失Vbeta8.2+细胞而抑制自身抗体的产生，从而改善自身免疫性疾病，并支持病毒SAG在基因治疗中的应用。

项目成果

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Suzuki,A.,Enari,M.,Eguchi,Y.,Matsuzawa,A.: "Involvement of Fas in regression of vaginal epithelia after ovariectomy and during an estrus cycle" EMBO Journal. 15. 211-215 (1996)

Suzuki,A.、Enari,M.、Eguchi,Y.、Matsuzawa,A.：“Fas 在卵巢切除术后和发情周期期间阴道上皮退化中的作用”EMBO 杂志。

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