Santucci L, Agostini M, Bruscoli S, Mencarelli A, Ronchetti S, Ayroldi E, Morelli A, Baldoni M, Riccardi C
Clinica di Gastroenterologia ed Epatologia, Dipartimento di Scienze Chirurgiche, Gastroenterologiche ed Epatologiche, Università di Perugia, Policlinico Monteluce, 06122 Perugia, Italy.
Gut. 2007 Jan;56(1):52-60. doi: 10.1136/gut.2006.091181. Epub 2006 Jun 8.
Uncontrolled T cell activation and abnormal function of the innate immune system against normal enteric bacterial flora play a critical part in the pathogenesis of inflammatory bowel disease (IBD). Therefore, pharmacological strategies directed to restore the normal responsiveness of the immune system could be efficacious in the treatment of these pathological conditions. Glucocorticoid-induced tumour necrosis factor receptor (GITR)-related gene is a member of the tumour necrosis factor receptor superfamily that is constitutively expressed at high levels on regulatory T cells and at low levels on unstimulated T cells, B cells and macrophages. GITR triggering leads to activation of T effectors and reversal of suppressive function of regulatory T cells.
To investigate the role of GITR in the development of experimental colitis in mice.
Using GITR(-/-) mice, GITR deletion protected against 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis by reducing innate immune responses and effector T cell activity. Effector T cells isolated from GITR(-/-) mice were less effective than T cells isolated from GITR(+/+) mice to transfer colitis in immunodeficient mice. Blocking the GITR/ligand for GITR (GITRL) signal by giving soluble GITR prevented TNBS-induced colitis in normal GITR(+/+) and also in lymphocyte-deficient SCID mice.
Collectively, these data suggest that GITR plays a critical part in regulating both acquired and innate mucosal immune responses during the development of experimental colitis in mice. Therefore, targeting the GITR/GITRL system signalling may represent a potential pharmacological tool for the treatment of IBD.
T细胞激活失控以及先天性免疫系统针对正常肠道菌群的功能异常在炎症性肠病（IBD）的发病机制中起关键作用。因此，旨在恢复免疫系统正常反应性的药理学策略可能对这些病理状况的治疗有效。糖皮质激素诱导的肿瘤坏死因子受体（GITR）相关基因是肿瘤坏死因子受体超家族的成员，在调节性T细胞上高水平组成性表达，在未刺激的T细胞、B细胞和巨噬细胞上低水平表达。GITR激活导致效应T细胞活化以及调节性T细胞抑制功能的逆转。
研究GITR在小鼠实验性结肠炎发生发展中的作用。
使用GITR基因敲除（GITR-/-）小鼠，GITR缺失通过降低先天性免疫反应和效应T细胞活性预防2,4,6-三硝基苯磺酸（TNBS）诱导的结肠炎。从GITR-/-小鼠分离的效应T细胞在免疫缺陷小鼠中转移结肠炎的效果不如从GITR+/+小鼠分离的T细胞。通过给予可溶性GITR阻断GITR/ GITR配体（GITRL）信号可预防正常GITR+/+小鼠以及淋巴细胞缺陷的SCID小鼠发生TNBS诱导的结肠炎。
总体而言，这些数据表明GITR在小鼠实验性结肠炎发生发展过程中对获得性和先天性黏膜免疫反应的调节中起关键作用。因此，靶向GITR/GITRL系统信号传导可能是治疗IBD的一种潜在药理学手段。
