Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation
Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation
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DOI：
10.1001/archopht.126.1.71
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发表时间：
2008-01-01
影响因子：
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通讯作者：
Cursiefen, Claus
中科院分区：
文献类型：
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作者：
Bachmann, Bjoern O.;Bock, Felix;Cursiefen, Claus
目的：探讨BALB/c小鼠角膜移植后，血管生成、淋巴管生成和单核巨噬细胞的侵袭是否会增加发生免疫排斥反应的风险。拆线后3周行角膜移植(供体为C57BL/6小鼠)。治疗组术后0、4、7、14d分别给予血管内皮生长因子A(VEGF-A)中和细胞因子TRAP(Fc蛋白作为对照)。用淋巴管内皮细胞透明质酸受体-1(淋巴管内皮细胞特异性标记物)、CD31(全内皮细胞标记物)和F4/80(单核巨噬细胞标记物)对角膜扁平片进行形态测量。结果：角膜移植后，观察到显著增加的血管生成(平均血管覆盖面积术后为68%[18%]vs术前40%[18%]；P=0.03)和淋巴管生成[术后12%[1.3%]vs术前9%[2.8%]；P=.03)。术后中和血管内皮生长因子-A抑制了手术诱导的血管生成(35%[8%]；P=.007)和淋巴管生成(6%[1.6%]；P=.03)，并减少了单核巨噬细胞在移植物中的募集(平均[SD]，治疗组小鼠为501个/mm(2)[152]vs FC对照组684个/mm(2)[35]；P=.03)。8周后，治疗组23%的角膜未发生排斥反应，而对照组21天后全部发生排斥反应(P=0.007)。结论：高危角膜移植后中和VEGF-A可有效抑制术后血管生成、淋巴管生成和抗原提呈细胞的募集，提高角膜移植物存活率。临床意义：阻断高危角膜移植后的VEGF-A可能是提高移植物存活率的新方法。
Objective: To evaluate whether hemangiogenesis, lymphangiogenesis, and concomitant invasion of mononuclear phagocytes occurring after high-risk corneal transplantation in already vascularized high-risk recipient corneal beds increase the risk for subsequent immune rejection.Methods: Three intrastromal sutures were left in place for 6 weeks in the corneas of BALB/c mice, causing neo-vascularization. Three weeks after suture removal, keratoplasty was performed (donors C57BL/6 mice). The treatment group received a vascular endothelial growth factor A (VEGF-A)-neutralizing cytokine trap at 0, 4, 7, and 14 days postoperatively (Fc protein was used as the control treatment). Morphometry was performed in corneal flat mounts using lymphatic endothelial hyaluronan receptor-1 (a specific lymphatic endothelial marker), CD31 (a panendothelial marker), and F4/80 (a marker for mononuclear phagocytes).Results: After corneal transplantation, significant additional hemangiogenesis (mean area covered by vessels [SDI, 68% [18%] postoperatively vs 40% [ 18%] preoperatively; P=.03) and lymphangiogenesis (12% [1.3%] postoperatively vs 9% [2.8%] preoperatively; P=.03) were observed. Postoperative neutralization of VEGF-A inhibited operation-induced hemangiogenesis (35% [8%]; P=.007) and lymphangiogenesis (6% [1.6%]; P=.03) and decreased the recruitment of mononuclear phagocytes into the graft (mean [SD], 501 cells/mm(2) [152] in treated mice vs 684 cells/mm(2) [35] in Fc controls; P=.03). After 8 weeks, 23% of the treated corneas were not rejected, whereas all control corneas were rejected after 21 days (P=.007).Conclusions: Neutralization of VEGF-A after high-risk corneal transplantation effectively inhibits postoperative hemangiogenesis, lymphangiogenesis, and recruitment of antigen-presenting cells and improves corneal graft survival.Clinical Relevance: Blocking of VEGF-A after high-risk corneal transplantation may be a novel approach to improve graft survival.