title: Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease.
abstract: OBJECTIVE
  The contribution of lymphangiogenesis (LA) to allergy has received considerable attention and therapeutic inhibition of this process via targeting VEGF has been considered. Likewise, certain inflammatory settings affecting the ocular mucosa can trigger pathogenic LA in the naturally avascular cornea. Chronic inflammation in allergic eye disease (AED) impacts the conjunctiva and cornea, leading to sight threatening conditions. However, whether corneal LA is involved is completely unknown. We addressed this using a validated mouse model of AED.
  
  
  METHODS
  Allergic eye disease was induced by ovalbumin (OVA) immunization and chronic OVA exposure. Confocal microscopy of LYVE-1-stained cornea allowed evaluation of corneal LA, and qRT-PCR was used to evaluate expression of VEGF-C, -D, and -R3 in these mice. Administration of VEGF receptor (R) inhibitor was incorporated to inhibit corneal LA in AED. Immune responses were evaluated by in vitro OVA recall responses of T cells, and IgE levels in the serum.
  
  
  RESULTS
  Confocal microscopy of LYVE-1-stained cornea revealed the distinct presence of corneal LA in AED, and corroborated by increased corneal expression of VEGF-C, -D, and -R3. Importantly, prevention of corneal LA in AED via VEGFR inhibition was associated with decreased T helper two responses and IgE production. Furthermore, VEGFR inhibition led a significant reduction in clinical signs of AED.
  
  
  CONCLUSIONS
  Collectively, these data reveal that there is a distinct involvement of corneal LA in AED. Furthermore, VEGFR inhibition prevents corneal LA and consequent immune responses in AED.
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Deniz
authors.initials: D
authors.lastname: Hos
authors.affiliation: Duke University School of Medicine, Department of Ophthalmology, Durham, North Carolina, United States.
authors.forename: Tomas
authors.initials: T
authors.lastname: Blanco
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Bock
authors.affiliation: Duke University School of Medicine, Department of Ophthalmology, Durham, North Carolina, United States.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Reyes
authors.affiliation: Duke University School of Medicine, Department of Ophthalmology, Durham, North Carolina, United States.
authors.forename: Rose
authors.initials: R
authors.lastname: Mathew
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Cursiefen
authors.affiliation: Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
authors.affiliation: Duke University School of Medicine, Department of Ophthalmology, Durham, North Carolina, United States 4Duke University School of Medicine, Department of Immunology, Durham, North Carolina, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Saban
mesh_terms: D000818:Animals; D000077784:Axitinib; D003315:Cornea / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007073:Immunoglobulin E / Q000097:blood; D007191:Indazoles / Q000494:pharmacology; D007637:Keratoconjunctivitis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D042583:Lymphangiogenesis / Q000502:physiology*; D042601:Lymphatic Vessels / Q000503:physiopathology*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D010047:Ovalbumin / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000037:antagonists & inhibitors / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000077784:Axitinib; D006023:Glycoproteins; D007093:Imidazoles; D007073:Immunoglobulin E; D007191:Indazoles; D026901:Membrane Transport Proteins; D010047:Ovalbumin; D047428:Protein Kinase Inhibitors; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D; D040321:Vascular Endothelial Growth Factor Receptor-3; C492273:LYVE1 protein, mouse