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F. Bock, D. Hos, T. Dietrich, J. Onderka, B. Bachmann, F. E. Kruse, S. J. Wiegand, C. Cursiefen; Lymphatic Vessels Determine the High-Risk Status of Vascularized Recipient Corneas. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1484.
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High-risk keratoplasties are defined by a prevascularized recipient cornea which increases the rate of graft rejection triggered by an immune response. Aim of this work was to analyze the relative importance of pathologic pre-existing lymphatic vessels, the afferent arm of the immune response arc, versus pre-existing blood vessels ("efferent arm") during engraftment of corneal transplants.
The murine model of high-risk keratoplasty was used by placing three interrupted 11-0 sutures into the corneal stroma of BALB/c mice and leaving them in place for 2 weeks. Mice in the treatment groups received either VEGF TrapR1R2 (25 mg/kg, intraperitoneally) as an inhibitor of both hem- and lymphangiogenesis (thus creating "avascular high-risk beds") or the blocking VEGFR3 antibody F4-31C1 (25 mg/kg, intraperitoneally) as a specific inhibitor of lymphangiogenesis (thus creating "alymphatic, but hemvascularized high-risk recipient beds") on the day of suture placement as well as 3, 5 and 7 days later. After two weeks sutures were removed and penetrating keratoplasty was performed with C57BL/6 donors (all mice female). Postoperative survival of the grafts was analyzed using Kaplan-Meier survival curves.
The survival of the grafts after high-risk keratoplasty was improved significantly by pretreatment with both the VEGF Trap R1R2 (p< 0.0001) and the VEGFR3 antibody (p< 0.0002) in the vascularisation phase prior to keratoplasty in comparison to the control groups.
Both blood and lymphatic vessels play a crucial role in defining a high-risk bed prior to keratoplasty. Since there was no significant difference between "avascular" and only "hemvascularized" high-risk beds we suggest pre-existing lymphatic vessels to play a more important role in determining the fate of a graft after high-risk keratoplasty. Therapeutically, blockade of lymphatic vessels prior to keratoplasty therefore could improve graft survival after subsequent corneal transplantation.
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