title: VEGF-trap aflibercept significantly improves long-term graft survival in high-risk corneal transplantation.
abstract: BACKGROUND
  Graft failure because of immune rejection remains a significant problem in organ transplantation, and lymphatic and blood vessels are important components of the afferent and efferent arms of the host alloimmune response, respectively. We compare the effect of antihemangiogenic and antilymphangiogenic therapies on alloimmunity and graft survival in a murine model of high-risk corneal transplantation.
  
  
  METHODS
  Orthotopic corneal transplantation was performed in hemevascularized and lymph-vascularized high-risk host beds, and graft recipients received subconjunctival vascular endothelial growth factor (VEGF)-trap, anti-VEGF-C, sVEGFR-3, or no treatment, beginning at the time of surgery. Fourteen days after transplantation, graft hemeangiogenesis and lymphangiogenesis were evaluated by immunohistochemistry. The frequencies of Th1 cells in regional lymphoid tissue and graft-infiltrating immune cells were evaluated by flow cytometry. Long-term allograft survival was compared using Kaplan-Meier curves.
  
  
  RESULTS
  VEGF-trap significantly decreased graft hemangiogenesis as compared to the control group and was most effective in reducing the frequency of graft-infiltrating immune cells. Anti-VEGF-C and sVEGFR3 significantly decreased graft lymphangiogenesis and lymphoid Th1 cell frequencies as compared to control. VEGF-trap (72%), anti-VEGF-C (25%), and sVEGFR-3 (11%) all significantly improved in the 8-week graft survival compared to control (0%), although VEGF-trap was significantly more effective than both anti-VEGF-C (P < 0.05) and sVEGFR-3 (P < 0.05).
  
  
  CONCLUSIONS
  In a clinically relevant model of high-risk corneal transplantation in which blood and lymphatic vessels are present and treatment begins at the time of transplantation, VEGF-trap is significantly more effective in improving long-term graft survival as compared to anti-VEGF-C and sVEGFR-3, but all approaches improve survival when compared to untreated control.
authors.affiliation: 1 Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, MA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Dohlman
authors.forename: Masahiro
authors.initials: M
authors.lastname: Omoto
authors.forename: Jing
authors.initials: J
authors.lastname: Hua
authors.forename: William
authors.initials: W
authors.lastname: Stevenson
authors.forename: Sang-Mok
authors.initials: SM
authors.lastname: Lee
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016039:Corneal Transplantation / Q000009:adverse effects*; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D042583:Lymphangiogenesis / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects; D040262:Receptors, Vascular Endothelial Growth Factor / Q000494:pharmacology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; C467480:vascular endothelial growth factor A, mouse; C467483:vascular endothelial growth factor C, mouse; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D040321:Vascular Endothelial Growth Factor Receptor-3