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

Using MRL/MpJ-lpr I D1 cg文件D1/lpr I D1 cg文件D1(lpr I D1 cg文件D1)mice，we produced lpr文件D1cg文件D1 mice carrying Vβ8.2-reactive viral superantigen(vSAG lpr文件D1)，those deficient in the membrane-bound CD4molecule by introducing a mutant gene(CD4-lpr文件D1)，those transgenic for the IL-pducing a mutant gene(CD4-lpr D1cg文件D1)，those transgenic for the IL-12pg D1crAnd those targeted for IL-1α/βgenes(IL-1-lpre D1)to investigate the roles or T cells and cytokines in the development of autoimmune manifestations.In vSAG lpr I D1cg i D1 and CD4-lpr D 1 cg i D 1 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-γwere generally decreased in the blood.The glomerular IC deposition in the kidney and the content or B220 I D1 I D 1 CD 4 I D 1-I D 1 CD 8 T cells in lymph nodes were markedly reduced.The results indicate that Vβ8.2 CD4T 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 p40lpr锡D1cg齐埃D1mice，the blood p40level 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-γwas suppressed compared to wild-type lpr y D1cg，suggesting that p40might suppress the functions of Th1cells througits inhibitory activagainst 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 i D1cg i D1mice，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：Less

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