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 mice /lpr - D1cg micewe produced lpr D1cg D1 mice carrying vβ 8.2-reactive viral superantigen (vSAG+lpr D1cg D1)，those deficient in the membran -bound CD4 molecule by introducing a mutant gene （CD4-lpr - D1cg - D1）those transgenic for the IL-12p40 gene （p4D+lpr - D1cg - D1）and those targeted for IL-1α/β genes (IL-1 lpr D1cg D1) to investigate the roles or T cells andcytokines in the development of autoimmune manifestations. in vSAG+lprCD4-lpr - D1cg - D1 mice，clinical symptoms including proteinuria and glomerulonephritis clearly improved andlymphadenopathy was ameliorated. Immunoglobulin，autoreactive factors such as immune complexes (IC), antinuclear antibodies and anti-DNA antibodies，and INF- generally decreased in the blood. the glomerular IC deposition in the kidney and thecontent or B220 - D1CD4 - D1CD8T cells in lymph nodes were markedly reduced. The resultsindicate that vβ 8.2+CD4+T cells p…lay a crucial role in the development or autoimmune diseases and that their depletionleads to the reduced glomerulonephritis resulting from the suppressed production of autoreactivefactors. In p40+lpr D1cg D1 mice, the blood p40 level were several thousand times higher，the level or a representative autoantibody, anti-DNAdecreased in the IgG2a but rather increased in the IgG1 subclass，and the production or INF-γ was suppressed compared to wild-type lpr D1cg D1 mice，suggesting that p40 might suppress the functions of Th1 cells through its inhibitory activityagainst IL-12. Although proteinuria and survival were slightly improved，the effects on IC production, lymphadenopathyglomerulonephritis and vasculitis were minimal or insignificant. In IL-1-lprthe clinical manifestations not improved at all, unexpectedlylymphoproliferation was markedly enhanced. Based on these results我们已经包括了gene therapies targeting T cells are than those targetingcytokines . 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