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急性同种异体移植排斥过程中的作用，并探索抗血管生成疗法作为小肠移植中新型移植后治疗的潜力。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。 C57BL/6 (H-2b) 用作供体，BALB/c (H-2d) 用作受体，移植后 7 天取出移植物并进行检查。在排斥小肠移植物中发现大量细胞浸润以及严重的组织破坏，表明 VEGF 和 VEGF 受体在同种异体移植物排斥过程中上调，表明 VEGF-VEGFR 相互作用在同种免疫反应中发挥一定作用。为了阐明潜在的机制，我们进一步用抗 VEGFR1 mAb 和/或抗 VEGFR2 mAb 治疗受体小鼠，尽管 VEGFR-1 或 VEGFR-2 阻断。并没有延长同种异体移植物的存活，同时阻断两种 VEGFR 显着预防急性同种异体移植物排斥并延长同种异体移植物存活。组织学分析也证实了同时阻断 VEGFR 对急性同种异体移植物排斥的保护作用。 -1 和 VEGFR-2 具有重要的功能，并且 VEGF/VEGFR 通路在同种免疫反应中发挥关键作用，此外，其效果与免疫反应显着相关。我们的数据表明，VEGF 可能通过两种不同的主要受体在体内同种免疫反应中起作用：VEGFR-1 和 VEGFR-2 靶向 VEGF-VEGFR 通路可能代表一种保护同种免疫反应的新疗法。此外，为了扩展我们的研究，我们测试了 VEGF 和 VEGFR 在缺血/再灌注损伤中的功能。缺血/再灌注损伤和 VEGFR 阻断可显着保护肝脏和小肠的缺血性损伤。这些数据表明，靶向 VEGF/VEGFR 可能代表临床移植的一种新策略。