Lovett-Racke Amy E, Rocchini Anne E, Choy Judy, Northrop Sara C, Hussain Rehana Z, Ratts Robert B, Sikder Devanjan, Racke Michael K
Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 USA.
Immunity. 2004 Nov;21(5):719-31. doi: 10.1016/j.immuni.2004.09.010.
As a means of developing therapies that target the pathogenic T cells in multiple sclerosis (MS) without compromising the immune system or eliciting systemic side effects, we investigated the use of T-bet-specific antisense oligonucleotides and small interfering RNAs (siRNA) to silence T-bet expression in autoreactive encephalitogenic T cells and evaluated the biological consequences of this suppression in experimental autoimmune encephalomyelitis, a model for MS. The T-bet-specific AS oligonucleotide and siRNA suppressed T-bet expression, IFNgamma production, and STAT1 levels during antigen-specific T cell differentiation. In vitro suppression of T-bet during differentiation of myelin-specific T cells and in vivo administration of a T-bet-specific antisense oligonucleotide or siRNA inhibited disease. T-bet was shown to bind the IFNgamma and STAT1 promoters, but did not regulate the IL-12/STAT4 pathway. Since T-bet regulates IFNgamma production in CD4(+) T cells, but to a lesser extent in most other IFNgamma-producing cells, T-bet may be a target for therapeutics for Th1-mediated diseases.
作为开发针对多发性硬化症（MS）中致病性T细胞的疗法的一种手段，同时又不损害免疫系统或引发全身性副作用，我们研究了使用T-bet特异性反义寡核苷酸和小干扰RNA（siRNA）来沉默自身反应性致脑炎性T细胞中的T-bet表达，并在实验性自身免疫性脑脊髓炎（一种MS模型）中评估这种抑制的生物学后果。T-bet特异性反义寡核苷酸和siRNA在抗原特异性T细胞分化过程中抑制了T-bet表达、IFNγ产生和STAT1水平。在髓鞘特异性T细胞分化过程中对T-bet进行体外抑制，以及在体内施用T-bet特异性反义寡核苷酸或siRNA均抑制了疾病。研究表明，T-bet可结合IFNγ和STAT1启动子，但不调节IL-12/STAT4途径。由于T-bet在CD4(+) T细胞中调节IFNγ产生，但在大多数其他产生IFNγ的细胞中作用较小，因此T-bet可能是Th1介导疾病治疗的一个靶点。
