ROLE OF ANGIOGENESIS AND POTENTIAL OF ANTIANGIOGENESIS AS POSTTRANPLANT TREATMENT IN SMALL BOWEL TRANSPLANTATION

本文旨在阐明血管生成在小肠移植急性排斥反应中的作用，并探讨抗血管生成治疗作为小肠移植术后新的治疗手段的可能性。为此，我们利用显微外科技术建立了完全MHC不匹配的小鼠小肠移植模型。以C57 BL/6（H-2b）为供体，BALB/c（H-2d）为受体。移植后第7天取出移植物进行检查。组织学检查显示，大量的细胞浸润以及严重的组织破坏被确定在排斥小肠移植。实时荧光定量PCR分析表明，VEGF和VEGF受体在同种异体排斥反应过程中表达上调，提示VEGF-VEGFR相互作用在同种异体免疫应答中起一定作用。为了阐明潜在的机制，我们进一步用抗VEGFR 1 mAb和/或抗VEGFR 2 mAb治疗受体小鼠。尽管VEGFR-1或VEGFR-2阻断均不能延长同种异体移植物的存活时间， ...更多信息 同时阻断两种VEGF受体可显著预防急性同种异体移植排斥反应，延长同种异体移植物存活。组织学分析也证实了同时阻断VEGF受体对急性同种异体移植排斥反应的保护作用。这些结果提示VEGFR-1和VEGFR-2在同种异体免疫应答中具有重要的功能，VEGF/VEGFR通路在同种异体免疫应答中起着关键作用。此外，该作用与局部细胞因子和趋化因子表达的下调显著相关。我们的数据表明，VEGF可能通过两种不同的主要受体：VEGFR-1和VEGFR-2在体内同种免疫反应中发挥作用。靶向VEGF-VEGFR通路可能成为临床移植中保护同种免疫应答的新疗法。此外，为了扩展我们的研究，我们检测了VEGF和VEGFR在缺血/再灌注损伤中的作用。数据还表明，VEGF在缺血/再灌注损伤中起重要作用，并且阻断VEGF受体显著保护肝脏和小肠中的缺血性损伤。这些数据表明，靶向VEGF/VEGFR可能代表临床移植的新策略。少

We tried to clarify the role of angiogenesis in the process of acute allograft rejection and explore the potential of antiangiogenic therapy as novel posttransplant treatment in small bowel transplantation. To this end, we utilized a fully MHC mismatched murine small bowel transplantation model using microsurgical technique. C57BL/6 (H-2b) were used as donor and BALB/c (H-2d) as recipient. The graft were removed and examined on 7 day after transplantation. Histological evaluation revealed that massive cellular infitration as well as the severe tissue destruction were identified in rejecting small bowel grafts. Realtime PCR analysis indicated that VEGF and VEGF receptors were upregulated in the process of allograft rejection suggesting that VEGF-VEGFR interaction has some roles in alloimmune response. To clarify the underlying mechanisms, we further treated recipient mice with anti-VEGFR1 mAb and/or anti-VEGFR2 mAb. Although either VEGFR-1 or VEGFR-2 blockade didn't prolong allograft su … More rvival, the simultaneous blockade of both VEGFRs significantly prevented acute allograft rejection and prolonged allograft survival. Histological analysis also confirmed the protective effect of simultaneous blockade of VEGFRs on acute allograft rejection. These findings are suggestive that both VEGFR-1 and VEGFR-2 are functionally important and VEGF/VEGFR pathway play critical roles in alloimmune response. Furthermore, the effect was significantly associated with the downregulation of local cytokine and chemokine expressions. Our data demonstrates that VEGF may function in alloimmune response in vivo via two distinct major receptors : VEGFR-1 and VEGFR-2. Targeting VEGF-VEGFR pathway may represent a novel therapy for the protection of alloimmune response in clinical transplantation. Furthermore, to extend our study, we tested the function of VEGF and VEGFR in ischemia/reperfusion injury. Data also suggested that VEGF plays an important role in ischemia/reperfusion injury and blockade of VEGFRs significantly protected ischemic injury in the liver and the small intestine. These data suggested that targeting VEGF/VEGFR might represent a novel strategy in clinical transplantation. Less