New Therapy with CXCL16 Blocking for Inflammatory Bowel Disease

（背景与目的）CXCL 16选择性表达于树突状细胞和巨噬细胞等APC细胞上。CXCL 16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作用，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。在这方面，推测APC和T细胞之间通过CXCL 16响应于各种刺激（例如腔细菌组分）的相互作用涉及IBD的病理生理学可能是有趣的。因此，本研究的目的是检查CXCL 16的调节是否对炎症性肠病有效。（方法）建立CXCL 16基因敲除小鼠模型，制备抗CXCL 16单克隆抗体IgG 1和抗人CXCL 16单克隆抗体。诱发结肠炎：为了诱导结肠炎，给予C57 BL/6小鼠在其饮用水中的3%DSS（mol wt，36-50千道尔顿）5天（从第0天至第4天）。TNBS结肠炎通过使用Neurath et. A1.抗CXCL 16 mAb治疗后的临床评价：诱导结肠炎后，给小鼠注射500μg抗CXCL 16 mAb或对照大鼠IgG。连续5d（结果）在DSS和TNBS结肠炎模型中，抗CXCL 16抗体的施用显著降低了结肠炎症的严重程度。在用抗CXCL 16抗体处理的组中，来自肠系膜淋巴结细胞的TNF-α和IFN-γ的产生将显著低于未处理组。抗CXCL 16治疗组小鼠MLN中CD 4 ^+ CD 69 ^+ T细胞的数量显著低于未治疗组。这些结果表明，CXCL 16是最重要的趋化因子之一，它参与了肠道炎症。结论CXCL 16活性异常是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.