Klemann Christian, Raveney Benjamin J E, Klemann Anna K, Ozawa Tomoko, von Hörsten Stephan, Shudo Koichi, Oki Shinji, Yamamura Takashi
Director, Department of Immunology, or Shinji Oki, Ph.D., Section Chief, Department of Immunology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
Am J Pathol. 2009 Jun;174(6):2234-45. doi: 10.2353/ajpath.2009.081084. Epub 2009 Apr 23.
Recent evidence suggests that interleukin-17-producing CD4(+) T cells (Th17 cells) are the dominant pathogenic cellular component in autoimmune inflammatory diseases, including multiple sclerosis. It has recently been demonstrated that all-trans retinoic acid can suppress Th17 differentiation and promote the generation of Foxp3(+) regulatory T cells via retinoic acid receptor signals. Here, we investigated the effects of AM80, a synthetic retinoid with enhanced biological properties to all-trans retinoic acid, on Th17 differentiation and function and evaluated its therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. AM80 treatment was more effective than all-trans retinoic acid in inhibiting Th17 differentiation in vitro. Oral administration of AM80 was protective for the early development of EAE and the down-modulation of Th17 differentiation and effector functions in vivo. Moreover, AM80 inhibited interleukin-17 production by splenic memory T cells, in vitro-differentiated Th17 cells, and central nervous system-infiltrating effector T cells. Accordingly, AM80 was effective when administered therapeutically after the onset of EAE. Continuous AM80 treatment, however, was ineffective at inhibiting late EAE symptoms despite the maintained suppression of RORgammat and interleukin-17 expression levels by central nervous system-infiltrating T cells. We reveal that continuous AM80 treatment also led to the suppression of interleukin-10 production by a distinct T cell subset that expressed both Foxp3 and RORgammat. These findings suggest that retinoid signaling regulates both inflammatory Th17 cells and Th17-like regulatory cells.
近期证据表明，产生白细胞介素-17的CD4(+) T细胞（Th17细胞）是包括多发性硬化症在内的自身免疫性炎症疾病中主要的致病性细胞成分。最近有研究表明，全反式维甲酸可通过维甲酸受体信号抑制Th17分化并促进Foxp3(+)调节性T细胞的生成。在此，我们研究了AM80（一种生物活性比全反式维甲酸更强的合成类维生素A）对Th17分化和功能的影响，并评估了其在实验性自身免疫性脑脊髓炎（EAE，一种多发性硬化症的动物模型）中的治疗潜力。在体外抑制Th17分化方面，AM80治疗比全反式维甲酸更有效。口服AM80对EAE的早期发展具有保护作用，并能在体内下调Th17分化和效应功能。此外，AM80可抑制脾脏记忆T细胞、体外分化的Th17细胞以及中枢神经系统浸润效应T细胞产生白细胞介素-17。因此，在EAE发病后进行治疗时，AM80是有效的。然而，尽管中枢神经系统浸润T细胞持续抑制RORγt和白细胞介素-17表达水平，但持续的AM80治疗在抑制EAE晚期症状方面无效。我们发现，持续的AM80治疗还导致一个同时表达Foxp3和RORγt的独特T细胞亚群产生白细胞介素-10受到抑制。这些发现表明，类维生素A信号传导可调节炎性Th17细胞和Th17样调节细胞。
