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

血管生成的作用以及抗血管生成作为小肠移植术后治疗的潜力

• 批准号: 15591891
• 负责人: KANEHIRO Hiromichi
• 金额: $ 2.24万
• 依托单位: NARA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591891/
• 关键词: SMALL BOWEL TRANSPLANTATION; ANGIOGENESIS; REJECTION; CARDIAC TRANSPLANTATION; VEGF

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

我们试图阐明血管生成在同种异体移植急性排斥反应过程中的作用，并探索抗血管生成治疗作为移植后新的治疗方法在小肠移植中的潜力。为此，我们利用显微外科技术建立了一种MHC完全不匹配的小鼠小肠移植模型。供体为C57BL/6(H-2b)，受体为BALB/c(H-2d)。移植后7d取出移植物进行检查。组织学评估显示，在排斥小肠移植过程中发现大量的细胞感染和严重的组织破坏。实时荧光定量聚合酶链式反应分析显示，在移植排斥反应过程中，血管内皮生长因子及其受体表达上调，提示血管内皮生长因子-血管内皮生长因子受体相互作用在同种异体免疫反应中起一定作用。为了阐明其潜在的机制，我们进一步用抗VEGFR1mAb和/或抗VEGFR2 mAb治疗受体小鼠。尽管血管内皮生长因子受体-1或血管内皮生长因子受体-2的阻断不能延长同种异体移植的…存活时间更长的是，同时阻断两种血管内皮生长因子受体显著防止了移植物的急性排斥反应，延长了移植物的存活时间。组织学分析也证实了同时阻断VEGFRs对移植急性排斥反应的保护作用。这些结果提示，VEGFR-1和VEGFR-2在同种异体免疫反应中都具有重要的功能，而VEGFR/VEGFR通路在同种异体免疫反应中起着关键作用。此外，这种效应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，在体内，血管内皮生长因子可能通过两种不同的受体：VEGFR-1和VEGFR-2在同种异体免疫反应中发挥作用。靶向VEGF-VEGFR通路可能为临床移植中保护同种异体免疫反应提供一种新的治疗方法。此外，为了扩大我们的研究范围，我们还检测了血管内皮生长因子及其受体在缺血/再灌注损伤中的作用。研究还表明，血管内皮生长因子在缺血再灌注损伤中起重要作用，阻断血管内皮生长因子受体对肝脏和小肠的缺血损伤有明显的保护作用。提示靶向血管内皮生长因子/血管内皮生长因子受体可能是临床移植的一种新策略。较少

项目成果

Dual Role of Vascular Endothelial Growth Factor in Hepatic Ischemia-Reperfusion Injury

• DOI: 10.1097/01.tp.0000161627.84481.5e
• 发表时间: 2005-05
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Y. Tsurui;M. Sho;Y. Kuzumoto;K. Hamada;S. Akashi;H. Kashizuka;N. Ikeda;T. Nomi;T. Mizuno;H. Kanehiro;Y. Nakajima