Study of mucosal immune response in the murine model of inflammatory bowel disease -Therapeutic effect of a new immunosuppressive reagent FTY720-

背景与目的：fty720是一种新型淋巴细胞归巢剂，具有较强的免疫抑制活性。FTY72O诱导的免疫抑制机制与传统免疫抑制剂完全不同，即加速淋巴细胞归巢。白细胞介素-10基因缺陷（IL-10^<-/->）小鼠在2-3月龄时自发发生小肠结肠炎，与人类克罗恩病在组织学上有许多相似之处。在本研究中，我们在IL-10 ^<-/->小鼠模型中检测了fty720治疗慢性结肠炎的疗效。方法：16 ~ 20周龄IL-10^<-/->，有结肠炎临床症状的小鼠口服FTY72O，剂量为0.3 mg/kg/d，连续4周。观察大鼠结肠的大体和组织学形态、固有层淋巴细胞的数量和表型以及淋巴细胞产生的细胞因子。结果：单次给药fty720可使Peyer’s patches和肠系膜淋巴结内循环淋巴细胞被隔离，外周血淋巴细胞数量相应减少。给药四周后，结肠炎严重程度显著降低，结肠固有层CD^<4+>淋巴细胞亚群显著减少，结肠淋巴细胞IFN-γ产生显著减少。结论：FTY720是一种新型淋巴细胞归巢剂，治疗成年小鼠可改善与人类克罗恩病有许多相似之处的IL-10^<-/->小鼠的慢性结肠炎。

Background & Aims: FTY72O is a novel lymphocyte homing agent that possesses potent immunosuppressive activity. The immunosuppression induced by FTY72O is mediated by completely different mechanisms from those of conventional immunosuppressants, i.e., by accelerated lymphocyte homing. Interleukin-10 gene- deficient (IL-10^<-/->) mice spontaneously develop an enterocolitis by 2-3 months of age that has many histologic similarities to human Crohn' sdisease. In this study, we examined the efficacy of FTY72O in the treatmentof chronic colitis in an IL-10 ^<-/-> mouse model.Methods: FTY72O was administered orally at a dose of 0.3 mg/kg/day for 4 weeks to 16-20-wk-old IL-10^<-/-> mice with clinical signs of colitis. The gross and histologic appearance of the colon, the numbers and phenotype of lamina propria lymphocytes, and cytokine production by the lymphocytes were compared with those characteristics in a control group.Results: Single-dose administration of FTY72O resulted in the sequestration of circulating lymphocytes within Peyer's patches and mesenteric lymph nodes, with a corresponding reduction in the numbers of lymphocytes in the peripheral blood. Four- week administration resulted in a significant decrease in the severity of colitis, accompanied by a significant reductionin the CD^<4+> lymphocyte subpopulation in the colonic lamina propria and in IFN-γ production by the colonic lymphocytes.Conclusions: FTY720, a novel lymphocyte homing agent, treatment of adult mice resulted in amelioration of established chronic colitis in IL-10^<-/->mice that have many similarities to human Crohn's disease.