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B. O. Bachmann, E. Luetjen-Drecoll, F. Bock, S. J. Wiegand, D. Hos, F. E. Kruse, C. Cursiefen; Administration of VEGF Trap After Keratoplasty in Corneas With Regressed Blood- and Lymphatic Vessels ("Low High-Risk" Corneas) Leads to Prolonged Graft Survival. Invest. Ophthalmol. Vis. Sci. 2007;48(13):194. doi: https://doi.org/.
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Neutralization of VEGF-A in the murine model of high-risk keratoplasty inhibits postoperative hem- and lymphangiogenesis and improves graft survival. Since in the clinical setting keratoplasty is not normally performed in freshly vascularised and inflamed eyes, but rather after an un-inflamed interval, we analyzed (a) the regression pattern of blood and lymphatic vessels after a short corneal inflammatory stimulus and (b) the ability of VEGF-A-blockade to inhibit postoperative revascularization into these "low high-risk eyes" and to improve graft survival.
Three interrupted 11-0 sutures were placed into the corneal stroma of BALB/c mice and left in place for 2-6 weeks. Six months after suture removal, corneas were either analyzed histomorphometrically for pathological corneal hem- and lymphangiogenesis (using LYVE-1 as a lymphatic endothelial specific marker and CD31 as a panendothelial marker) or penetrating keratoplasty was performed with C57BL/6 donors (all mice female). Mice in the treatment group received VEGF Trap (25 mg/kg, intraperitoneally) on the day of keratoplasty as well as 4, 7 and 14 days later. The VEGF Trap is a receptor-based fusion protein that binds all isoforms of VEGF-A, as well as placental growth factor; controls received an equal amount of Fc protein (n=10 per group). Postoperative survival of the grafts was analyzed using Kaplan-Meier survival curves.
Six months after suture removal, no intact lymphatic vessels were observed in the previously hem- and lymphvascularized corneas, whereas 10% of the corneal area remained pathologically vascularised (partly with non-perfused "ghost vessels"). Survival proportions after keratoplasty into these low high-risk eyes at day 14 were 10% in the control group and 83% in the treatment group. By day 21 all control corneas were rejected, whereas 83% of the treated corneas remained un-rejected.
After a temporary corneal inflammation, there is earlier and complete regression of lymphatic vessels compared to blood vessels. Inhibition of post-keratoplasty regrowth of regressed blood and lymphatic vessels by VEGF-A blockade can significantly prolong graft survival. This supports the concept of an important role for early postoperative induction of hem- and lymphangiogenesis in the mediation of immune responses after corneal transplantation.
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