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L Chen, P Hamrah, Q Zhang, MR Dana; VEGFR-3 in Cornea Lymphangiogenesis and APC Trafficking . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2268.
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Purpose: Previous data from this lab indicate that lymphatic flow from the cornea to draining lymph nodes (LN) plays an important role in corneal immunity. Specifically, corneal transplantation to BALB/c hosts that had their cervical LN excised before surgery showed indefinitely and universal graft acceptance (Yamagami S. & Dana M.R., 2001). VEGFR-3 (Flt-4) is a receptor tyrosine kinase which is mainly expressed on the lymphatic endothelium in adult tissues. The purpose of this study is to elucidate the expressional changes of VEGFR-3 during corneal neovascularization (NV) and its possible roles in cornea lymphangiogenesis and APC trafficking. Methods: Corneal NV was induced by intrastromal 11-0 nylon sutures in Balb/c mice. Eyes were procured 1, 3, 7, 14 days after the manipulation. Lymphatic vessels and VEGFR-3 positive cells were identified by confocal microscopy with immunofluorescence staining. Results: Cornea lymphatic vessels were detected with VEGFR-3 and CD31 double staining in corneal whole mounts starting at day 3 during induction of corneal NV. Cross sectional studies additionally revealed that the ocular surface epithelium of normal eyes express high levels of VEGFR-3. A sharp increase in VEGFR-3 staining in the corneal stroma was observed during the first week after induction of NV and a transient increase of VEGFR-3 expression on the epithelial layers of the limbus and conjunctival region around day 3 was also found. Additionally, corneal inflammation was associated with enhanced expression of VEGFR-3 by CD11c+ corneal dendritic cells. Conclusion: The expression of VEGFR-3 in the cornea and ocular surface is modified during corneal NV, both at the level of lymphatic vessels, and epithelial and stromal cells. These changes may affect trafficking of antigens and/or antigen-presenting cells from the eye to lymphoid organs and provide one explanation for why eyes with NV are considered 'high-risk' candidates for allograft survival. Additional studies including the use of recombinant VEGFR-3 chimeric protein in allograft cornea transplantation were undertaken to further define the possible functional roles of this receptor in lymphatic drainage and graft survival. Support: NIH/NEI Grant EY12963
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