title: Soluble vascular endothelial growth factor receptor-3 suppresses allosensitization and promotes corneal allograft survival.
abstract: OBJECTIVE
  To investigate the effect of VEGF-C and VEGF-D blockade via soluble VEGFR-3 (sVEGFR-3) on T cell allosensitization, corneal neovascularization, and transplant survival.
  
  
  METHODS
  Corneal intrastromal suture placement and allogeneic transplantation were performed on BALB/c mice to evaluate the effect of sVEGFR-3 on corneal neovascularization. Soluble VEGFR-3 trap was injected intraperitoneally to block VEGF-C/D (every other day starting the day of surgery). Immunohistochemical staining of corneal whole mounts was performed using anti-CD31 (PECAM-1) and anti-LYVE-1 antibodies to quantify the levels of hem- and lymphangiogenesis, respectively. Mixed lymphocyte reaction (MLR) was performed to assess indirect and direct host T cell allosensitization and the frequencies of IFN-γ-producing T cells in the draining lymph nodes were assessed using flow cytometry. Graft opacity and survival was evaluated by slit-lamp biomicroscopy.
  
  
  RESULTS
  Treatment with sVEGFR-3 resulted in a significant blockade of lymphangiogenesis 2 weeks post-transplantation and significantly prolonged corneal allograft survival compared to the control group at 8 weeks post-transplantation (87.5 % vs. 50 %), and this was associated with significant reduction in the frequencies of allosensitized T cells and decreased frequencies of IFN-γ-producing CD4 T cells.
  
  
  CONCLUSIONS
  Soluble VEGFR-3 suppresses corneal lymphangiogenesis and allograft rejection and may offer a viable therapeutic modality for corneal neovascularization and corneal transplantation.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA, 02114, USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Emami-Naeini
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Dohlman
authors.forename: Masahiro
authors.initials: M
authors.lastname: Omoto
authors.forename: Takaaki
authors.initials: T
authors.lastname: Hattori
authors.forename: Yihe
authors.initials: Y
authors.lastname: Chen
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Lee
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D003315:Cornea / Q000276:immunology*; D016510:Corneal Neovascularization / Q000276:immunology / Q000517:prevention & control*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D015948:Keratoplasty, Penetrating; D042583:Lymphangiogenesis / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D014184:Transplantation, Homologous; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors; D042643:Vascular Endothelial Growth Factor D / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000494:pharmacology*
chemical_list: D006023:Glycoproteins; D007519:Isoantigens; D026901:Membrane Transport Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; C492273:LYVE1 protein, mouse
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