New Therapy with CXCL16 Blocking for Inflammatory Bowel Disease

（背景与目的）CXCL16仅在树突状细胞和巨噬细胞等APC上选择性表达。CXCL16通过趋化因子结构域支持革兰氏阳性和阴性细菌的结合和吞噬，表明它可能参与促进各种病原体的摄取和APC-T细胞相互作用，以启动免疫应答。因此，APC与T细胞通过CXCL16响应各种刺激（如腔内细菌成分）的相互作用参与IBD的病理生理可能是一个有趣的推测。因此，本研究的目的是研究调节CXCL16是否对炎症性肠病有效。（方法）制备CXCL16敲除小鼠和抗cxcl16mabigg1和抗人cxcl16mab。诱导结肠炎：为诱导结肠炎，C57BL/6小鼠在其饮水中添加3%DSS （mol wt， 36-50千道尔顿）5天（从第0天至第4天）。采用改良Neurath等人方法诱导SJL/J小鼠TNBS结肠炎。抗cxcl16mab治疗后临床评价：诱导结肠炎后，小鼠注射500μg抗cxcl16mab或对照大鼠IgG。5天。（结果）抗cxcl16抗体可显著降低DSS和TNBS结肠炎模型的结肠炎症程度。抗cxcl16抗体治疗组的肠系膜淋巴结细胞TNF-α和IFN-γ的产生明显低于未治疗组。抗cxcl16治疗组小鼠MLN中CD4^+ CD69^+ T细胞的淋巴细胞数量明显低于未治疗组。这些发现表明CXCL16是参与肠道炎症的最重要的趋化因子之一。（结论）该数据首次证明CXCL16活性失调是人类IBD的重要致病因素之一。

(Background &Aim) CXCL16 is selectively expressed on only APC such as dendritic cells and macrophages. CXCL16 supports binding and phagocytosis of both gram-positive and negative bacteria through the chemokine-domain, suggesting that it may be involved in facilitating uptake of various pathogens and APC-T cell interactions in initiation of immune response. In this regard, it may be interesting to speculate that the interaction between APC and T cells through CXCL16 in response to various stimuli such as luminal bacteria components is involved in the pathophysiology of IBD. Therefore, the aim of the present study is to examine whether or not regulation of CXCL16 is effective for inflammatory bowel disease. (Methods) We generate CXCL16 knock out mice and anti-CXCL16mAbIgG1 and anti-human CXCL16mAbs. Induction of Colitis: To induce colitis, C57BL/6 mice are given 3%DSS (mol wt, 36-50 kilodaltons) in their drinking water for 5 days (from day 0 to 4). TNBS colitis is induced in SJL/J mice by using a modification of the method described by Neurath et. Al. Clinical evaluation after treatment by anti-CXCL16mAb: After induction of colitis, mice are injected with 500μg anti-CXCL16mAb or control rat IgG. For 5 days. (Results) Administration of anti-CXCL16 antibody dramatically decreased the severity of colonic inflammation in both DSS and TNBS colitis models. Production of both TNF-α and IFN-γ from mesenteric lymph node cells will be significantly lower in the group treated with anti-CXCL16 antibody than in non-treated group. The number of lymphocytes of CD4^+ CD69^+ T cells from the MLN in the mice treated with anti-CXCL16 was significantly lower than those in non-treated group. These finding suggested that CXCL16 is one of the most important chemokines, which is involved in the intestinal inflammation. (Conclusion) This data demonstrate the first evidence that dysregulation of CXCL16 activity is one of the important pathogenetic factor for human IBD.