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(Investigative Ophthalmology and Visual Science. 2004;45:2666-2673.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-1380
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Inhibition of Hemangiogenesis and Lymphangiogenesis after Normal-Risk Corneal Transplantation by Neutralizing VEGF Promotes Graft Survival

Claus Cursiefen,1,2,3 Jingtai Cao,4 Lu Chen,1 Ying Liu,1 Kazuichi Maruyama,1 David Jackson,5 Friedrich E. Kruse,3 Stanley J. Wiegand,4 M. Reza Dana,1 and J. Wayne Streilein1,6

1From The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; 4Regeneron Pharmaceuticals Inc., Tarrytown, New York; the 5Medical Research Council Human Immunology Unit, Institute of Molecular Medicine, Oxford, United Kingdom; and 3the Department of Ophthalmology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. 2Present affiliation: Department of Ophthalmology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

PURPOSE. To evaluate the occurrence and time course of hem- and lymphangiogenesis after normal-risk corneal transplantation in the mouse model and to test whether pharmacologic strategies inhibiting both processes improve long-term graft survival.

METHODS. Normal-risk allogeneic (C57BL/6 to BALB/c) and syngeneic (BALB/c to BALB/c) corneal transplantations were performed and occurrence and time course of hem- and lymphangiogenesis after keratoplasty was observed, by using double immunofluorescence of corneal flatmounts (with CD31 as a panendothelial and LYVE-1 as a lymphatic vascular endothelium–specific marker). A molecular trap designed to eliminate VEGF-A (VEGF TrapR1R2; 12.5 mg/kg) was tested for its ability to inhibit both processes after keratoplasty and to promote long-term graft survival (intraperitoneal injections on the day of surgery and 3, 7, and 14 days later).

RESULTS. No blood or lymph vessels were detectable immediately after normal-risk transplantation in either donor or host cornea, but hem- and lymphangiogenesis were clearly visible at day 3 after transplantation. Both vessel types reached donor tissue at 1 week after allografting and similarly after syngeneic grafting. Early postoperative trapping of VEGF-A significantly reduced both hem- and lymphangiogenesis and significantly improved long-term graft survival (78% vs. 40%; P < 0.05).

CONCLUSIONS. There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed. Inhibition of hem- and lymphangiogenesis (afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival, establishing early postoperative hem- and lymphangiogenesis as novel risk factors for graft rejection even in low-risk eyes.




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