Park Tae-Yoon, Park Sung-Dong, Cho Jen-Young, Moon Jae-Seung, Kim Na-Yeon, Park Kyungsoo, Seong Rho Hyun, Lee Sang-Won, Morio Tomohiro, Bothwell Alfred L M, Lee Sang-Kyou
Department of Biotechnology, College of Life Science and Biotechnology, Translational Research Center for Protein Function Control, Yonsei University, Seoul 120-749, Republic of Korea;
Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea;
Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18673-8. doi: 10.1073/pnas.1413687112. Epub 2014 Dec 19.
The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORγt) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORγt using cell-transducible form of transcription modulation domain of RORγt (tRORγt-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORγt-TMD specifically inhibited TH17-related cytokines induced by RORγt, thereby suppressing the differentiation of naïve T cells into TH17, but not into TH1, TH2, or Treg cells. tRORγt-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORγt-TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORγt-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORγt-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis.
核激素受体视黄酸相关孤儿受体γt（RORγt）是一种对产生白细胞介素（IL）-17的辅助性T细胞17（TH17细胞）具有特异性的转录因子，且与多种自身免疫性疾病有关。在此，我们开发了一种新的治疗策略，即使用RORγt转录调节结构域的细胞可转导形式（tRORγt-TMD）来调节RORγt的功能，该形式能够有效地递送至细胞核以及中枢神经系统（CNS）。tRORγt-TMD特异性抑制由RORγt诱导的TH17相关细胞因子，从而抑制初始T细胞向TH17细胞分化，但不影响其向TH1、TH2或调节性T细胞（Treg细胞）分化。将tRORγt-TMD注射到实验性自身免疫性脑脊髓炎（EAE）动物模型中，可有效地递送至脾脏CD4(+) T细胞和脊髓浸润性CD4(+) T细胞，并抑制TH17细胞的功能。tRORγt-TMD以预防和治疗方式改善了EAE的临床严重程度和发病率，并且观察到浸润到CNS中的CD4(+) IL-17(+) T细胞和炎性细胞均显著减少。结果，tRORγt-TMD治疗后脊髓脱髓鞘数量也减少了。基于同样的概念验证，特异性阻断TH1分化的tTbet-TMD改善了类风湿性关节炎（RA）的临床发病率。因此，tRORγt-TMD和tTbet-TMD可能是对与TH17或TH1相关的炎症性疾病具有天然特异性的新型治疗试剂。该策略可应用于治疗特定转录因子在发病机制中起关键作用的各种疾病。
