A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection
A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection
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DOI：
10.1097/01.tp.0000166338.99933.e1
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发表时间：
2005-08-15
期刊：
影响因子：
6.2
通讯作者：
Nakajima, Y
中科院分区：
文献类型：
--
作者：
Akashi, S;Sho, M;Nakajima, Y
背景趋化因子和趋化因子受体在白细胞募集、活化和分化中至关重要。其中CC趋化因子受体5（CCR 5）和CXC趋化因子受体3（CXCR 3）在同种异体免疫反应中起重要作用，可能成为移植后免疫抑制的潜在靶点。使用完全主要组织相容性复合体（MHC）错配的小鼠心脏和胰岛移植模型，通过靶向CCR 5和CXCR 3，检测新型小分子化合物TAK-779在急性同种异体移植排斥反应中的体内作用。采用MHC 11类抗原不匹配的心脏移植模型评价其在慢性移植排斥反应中的疗效。通过实时定量聚合酶链反应和组织学分析测定移植物内细胞因子、趋化因子和趋化因子受体的表达。在两种不同的移植模型中，TAK-779治疗显著延长了跨MHC屏障的同种异体移植物存活。如通过几种趋化因子、细胞因子和趋化因子受体的表达减少所观察到的，治疗下调局部免疫活化。因此，CD 4、CD 8和CD 11 c细胞向移植的同种异体移植物中的募集被抑制。此外，TAK-779治疗显著减弱了慢性血管病变、纤维化和细胞浸润的发展。CCR 5和CXCR 3的拮抗作用对抑制急性和慢性移植排斥反应具有显著的治疗效果。CCR 5和CXCR 3在同种异体移植排斥反应过程中发挥重要作用，有可能成为临床移植治疗的潜在靶点。
Background. Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression.Methods. Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class 11 mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis.Results. Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration.Conclusions. Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.