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

通过12代回交，将lpr^<cg>基因导入MRL小鼠，建立MRL-lpr^<cg>/lpr^<cg> (MRL-lpr^<cg>)小鼠。将它们的新生儿寄养在FM母鼠身上，建立携带编码vbeta8.2特异性超抗原（SAg）的小鼠乳腺肿瘤病毒（MMTV）的MRL-lpr^<cg>fFM。为期一年的调查显示，与MRL-lpr^<cg>相比，MRL-lpr^<cg>的fFM小鼠存活时间更长，蛋白尿水平更低。3个月和5个月大的尸检显示，MRL-lpr^<cg>fFM的淋巴增生性疾病较轻。组织学和免疫荧光检查显示，MRL-lpr^<cg>fFM组临床肾小球肾炎发生率明显低于MRL-lpr^<cg>组，且黏附免疫复合物的数量明显少于MRL-lpr^<cg>组。血清学分析显示，MRL-lpr^<cg>fFM小鼠总IgG水平和IgG类、IgG2a和IgG3亚类的抗dna抗体水平较低。在MRL-lpr^<cg>fFM小鼠的CD4+、CD8+和CD4-8- T细胞群中，Vbeta8.2+细胞几乎完全消失。这些结果证明MMTV (FM) SAg通过缺失Vbeta8.2+细胞来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。

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.