Inhibition of Angiogenesis and Lymphangiogenesis After High–Risk Keratoplasty by Neutralizing VEGF–A Improves Corneal Graft Survival

Abstract

Abstract: : Purpose: Pre–existing corneal blood and lymphatic vessels have long been identified as strong risk factors for immune rejections occurring after keratoplasty. Previously, we could demonstrate that inhibition of neovascularization after low–risk keratoplasty improves graft survival. The aim of this study was to evaluate whether additional angiogenesis and newly developed lymphangiogenesis after high–risk keratoplasty increase the risk for immune rejection after corneal grafting. Methods: Three interrupted 11–0 sutures were placed into the corneal stroma of BALBc mice for 6 weeks when the corneas were intensely vascularized. Sutures were removed. Three weeks later, penetrating keratoplasty was performed with same–aged C57BL/6 donors in the mouse model of corneal transplantation (all mice were female). Thirteen mice in the treatment group received a VEGF–A specific cytokine trap (VEGF Trap) intraperitoneally at day of surgery as well as 4, 7 and 14 days later (25 mg/kg/mouse; controls received an equal amount of Fc–protein; n=10). Postoperative survival of the grafts was analyzed for 8 weeks using a slit–lamp and Kaplan–Meier survival curves. Results: Survival proportions at day 14 were 10% in the control group and 46% in the treatment group. At day 21 all ten control corneas were already rejected whereas 31% of the treated corneas remained un–rejected. After 8 weeks, all control corneas remained rejected, whereas 23% (3) of the treated corneas were still un–rejected (p<0.05). Conclusions: Inhibition of hem– and lymphangiogenesis after high–risk keratoplasty improves corneal graft survival establishing postkeratoplasty neovascularization as a risk factor for immune rejections even in prevascularized high–risk eyes. These data support the new concept that modulation of surgery–related hem– and lymphangiogenesis after keratoplasty can improve graft outcome.

Keywords: transplantation • immunomodulation/immunoregulation • wound healing