Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology.
OBJECTIVE
The normal cornea is devoid of blood and lymphatic vessels but can become vascularized secondary to a variety of corneal diseases and surgical manipulations. Whereas corneal (hem)angiogenesis, i.e., the outgrowth of new blood vessels from preexisting limbal vessels, is obvious both clinically and histologically, proof of associated corneal lymphangiogenesis has long been hampered by invisibility and lack of specific markers. This has changed with the recent discovery of the lymphatic endothelial markers vascular endothelial growth factor receptor 3, LYVE-1 (a lymphatic endothelium-specific hyaluronan receptor), Prox 1, and Podoplanin.


METHODS
We herein summarize the current evidence for lymphangiogenesis in the cornea and describe its molecular markers and mediators. Furthermore, the pathophysiologic implications of corneal lymphangiogenesis for corneal transplant immunology are discussed.


RESULTS
Whereas corneal angiogenesis in vascularized high-risk beds provides a route of entry for immune effector cells to the graft, lymphangiogenesis enables the exit of antigen-presenting cells and antigenic material from the graft to regional lymph nodes, thus inducing alloimmunization and subsequent graft rejection.


CONCLUSIONS
Antilymphangiogenic strategies may improve transplant survival both in the high- and low-risk setting of corneal transplantation.
Cursiefen
Claus
C
The Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA. cursiefen@vision.eri.harvard.edu
Chen
Lu
L
Dana
M Reza
MR
Streilein
J Wayne
JW
D015415:Biomarkers / Q000032:analysis; D003316:Corneal Diseases / Q000276:immunology*; D016039:Corneal Transplantation / Q000276:immunology*; D004729:Endothelium, Lymphatic / Q000378:metabolism; D006085:Graft Survival; D006801:Humans; D008208:Lymphatic System / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000473:pathology
D015415:Biomarkers