Triggering endogenous immunosuppressive mechanisms by combined targeting of Dipeptidyl peptidase IV (DPIV/CD26) and Aminopeptidase N (APN/CD13) -: A novel approach for the treatment of inflammatory bowel disease
Triggering endogenous immunosuppressive mechanisms by combined targeting of Dipeptidyl peptidase IV (DPIV/CD26) and Aminopeptidase N (APN/CD13) -: A novel approach for the treatment of inflammatory bowel disease
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DOI：
10.1016/j.intimp.2006.09.014
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发表时间：
2006-12-20
影响因子：
5.6
通讯作者：
Ansorge, Siegfried
中科院分区：
文献类型：
--
作者：
Bank, Ute;Heimburg, Anke;Ansorge, Siegfried
外肽酶二肽基肽酶IV和丙氨酰氨肽酶N，强烈表达的两个，激活和调节T细胞被证明在T细胞调节合作。基于DPIV和APN抑制剂平行诱导TGF-β 1和IL-10产生和T辅助细胞增殖的抑制，以及特别是APN抑制剂放大调节性T细胞的抑制活性的发现，两种肽酶代表了用于治疗与不平衡T细胞应答相关的疾病的有希望的靶复合物，本研究的目的是分析DPIV和APN抑制剂在结肠炎小鼠模型中的体内治疗潜力。Balb/c小鼠在饮用水中接受3%（w/v）葡聚糖硫酸钠7天。在结肠炎症状发作后，在第3天开始抑制剂治疗。每天评估疾病活动指数（DAI），并辅以组织学和免疫学分析。虽然单独的DPIV抑制剂Lys-[Z（NO]）（2）]-吡咯烷或APN-抑制剂Actinonin具有显著但不显著的治疗效果，但与安慰剂治疗的小鼠相比，同时施用两种抑制剂显著降低了结肠炎活性（DAI 4.8对7.7，p < 0.005）。新开发的对两种酶都具有抑制能力的化合物IP 12.C6显著减轻了结肠炎的临床表现（DAI 3.2 vs.7.6，p < 0.0001）。TGF-β mRNA被发现上调，在结肠组织的coronor-treated animals.In总结，我们的研究结果强烈表明，DPIV和APN的合成抑制剂的联合抑制代表了一种新的和有效的方法，通过触发内源性免疫抑制机制的IBD的药物治疗。(c)2006 Elsevier B. V.保留所有权利。
The ectopeptidases Dipeptidylpeptidase IV and Alanyl-Aminopeptidase N, strongly expressed by both, activated and regulatory T cells were shown to co-operate in T cell regulation. Based on the findings that DPIV and APN inhibitors induce the TGF-beta 1 and IL-10 production and a suppression of T helper cell proliferation in parallel, and that particularly APN inhibitors amplify the suppressing activity of regulatory T cells, both peptidases represent a promising target complex for treatment of diseases associated with an imbalanced T cell response, such as inflammatory bowel diseases (IBD).The aim of the present study was to analyze the therapeutic potential of DPIV and APN inhibitors in vivo in a mouse model of colitis. Balb/c mice received 3% (w/v) dextran sulphate sodium with the drinking water for 7 days. After onset of colitis symptoms, inhibitor treatment started at day 3. Disease activity index (DAI) was assessed daily, supplemented by histological and immunological analysis. While the DPIV inhibitor Lys-[Z(NO])(2)]-pyrrolidide or the APN-inhibitor Actinonin alone had marked but no significant therapeutic effects, the simultaneous administration of both inhibitors reduced colitis activity in Comparison to placebo treated mice, significantly (DAI 4.8 vs. 7.7, p < 0.005). A newly developed compound IP12.C6 with inhibitory capacity toward both enzymes significantly attenuated the clinical manifestation of colitis (DAI 3.2 vs. 7.6,p < 0.0001). TGF-beta mRNA was found to be up-regulated in colon tissue of inhibitor-treated animals.In summary our results strongly suggest that combined DPIV and APN inhibition by synthetic inhibitors represents a novel and efficient approach for the pharmacological therapy of IBD by triggering endogenous immunosuppressive mechanisms. (c) 2006 Elsevier B.V. All rights reserved.