Function of the vascular endothelial growth factor receptors Flt-1 and Flk-1/KDR in the alloimmune response in vivo
Function of the vascular endothelial growth factor receptors Flt-1 and Flk-1/KDR in the alloimmune response in vivo
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DOI：
10.1097/01.tp.0000173650.83320.b1
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发表时间：
2005-09-27
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：
Sho, M;Akashi, S;Nakajima, Y
背景我们最近报道，血管内皮生长因子（VEGF）作为一种促炎细胞因子，在移植后早期调节白细胞进入同种异体移植物的运输。VEGF结合两种主要的VEGF受体：VEGFR-1（flt-1）和VEGFR-2（flk-1/KDR）。本研究旨在探讨VEGF受体在同种异体移植急性排斥反应中的表达及功能。我们将MHC完全不匹配的C57 BL/6（H-2（B））移植到BALB/c（H-2（d））血管化的小鼠异位心脏移植物中，并通过免疫组化检测急性同种异体排斥反应期间VEGF和VEGF受体的表达。接下来，我们用抗鼠VEGFR-1和VEGFR-2的特异性中和单克隆抗体治疗小鼠，并通过组织学和移植物存活分析来检查其对急性同种异体移植物排斥反应发展的影响。实时荧光定量PCR检测移植物内细胞因子和趋化因子的表达。VEGF、VEGFR-1和VEGFR-2的表达在移植排斥反应中较同系移植物显著上调。单独给予抗VEGFR-1或抗VEGFR-2均不能抑制同种异体移植排斥反应。然而，两种抗体共同给药抑制同种异体移植物的白细胞浸润和延长同种异体移植物存活。此外，VEGFR阻断的效果与移植物内细胞因子和趋化因子表达的下调有关。我们的数据表明VEGF-VEGFR相互作用在体内同种免疫应答中起作用。靶向VEGF受体可能是临床移植后保护同种异体移植物的一种新疗法。
Background. We have recently reported that vascular endothelial growth factor (VEGF) functions as a proinflammatory cytokine to regulate the trafficking of leukocytes into allografts in the early posttransplant period. VEGF binds two major VEGF receptors: VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR). Here, we wished to investigate the expression and function of VEGF receptors in the process of acute allograft rejection in vivo.Methods. We performed fully MHC-mismatched C57BL/6 (H-2(b)) into BALB/c (H-2(d)) vascularized heterotopic murine cardiac transplants and we examined the expression of VEGF and VEGF receptors by immunohistochemistry during acute allograft rejection. Next, we treated mice with specific neutralizing monoclonal antibodies against murine VEGFR-1 and VEGFR-2 and examined their effect on the development of acute allograft rejection by histology and by analysis of graft survival. The intragraft expression of cytokines and chemokines were also evaluated by quantitative real-time PCR analysis.Results. The expression of VEGF, VEGFR-1 and VEGFR-2 were significantly up-regulated during allograft rejection as compared to isografts. Administration of either anti-VEGFR-1 or anti-VEGFR-2 alone failed to inhibit allograft rejection. However, coadministration of both antibodies together inhibited leukocyte infiltration of allografts and prolonged allograft survival. Furthermore, the effect of VEGFR blockade was associated with the downregulation of intragraft cytokine and chemokine expression.Conclusions. Our data suggest that VEGF-VEGFR interactions function in the alloimmune response in vivo. Targeting VEGFRs may represent a novel therapy to protect allografts following clinical transplantation.