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T. Funaki, A. Hajrasouliha, Z. Sadrai, T. Hattori, R. Dana; Concomitant Blockade of Lymphatic and Blood Vessel Growth Into the Corneal Graft Improves Corneal Transplant Survival. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1554.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal transplantation is by far the most common form of solid tissue transplantation. The high success rate of corneal transplant is overshadowed by survival rates of well under 50% when grafts are placed in "high-risk" hosts whose recipient bed is inflamed and vascularized. However, because the presence of lymphatic vessels is undetectable by clinical slit lamp examination, unlike blood neovessels, the importance of lymphangic vessel growth in graft rejection may be underappreciated. We hypothesized that VEGF-C blockade can concomitantly suppress lymphatic and blood vessel growth in the cornea, reducing the leukocyte trafficking and thus promotes graft survival.
Micropellets loaded with bFGF were placed in BALB/c corneas. Angiogenic responses were analyzed by immunohistochemistry to quantify blood neovessels (CD31 high, LYVE-1-) and lymphatic neovessels (CD31low, LYVE-1+) to 2 weeks after implantation. Areas covered by BV and LV were calculated and expressed as a percentage of the total corneal area (percentage BV and percentage LV). The expression of VEGF receptors were quantified by RT-PCR. To block VEGF-C, intraperitoneal injections of anti-VEGF-C (VEG-100, Vegenics, Inc. 20 mg/kg) were started one day prior to surgery and continued on alternate days for 2 weeks. Allogeneic (C57BL/6 to Balb/c) corneal transplantation was performed and the effect of Anti-VEGF-C treatment (as described above) on donor and host leukocytes trafficking to draining lymph node was tested by flow cytometry. The graft survival was evaluated after 8 weeks of follow up.
Two weeks after corneal implantation of bFGF, blood vessels (44% reduction, P<0.001) and lymphatic growth (38% reduction, P<0.05) into cornea were significantly reduced after VEGF-C blockade. The expression of VEGF receptors were effectively suppressed by anti-VEGF-C treatment (p<0.01). Anti-VEGF-C treatment decreased donor and host leukocytes trafficking to draining lymph node of transplanted corneas, moreover doubled the cornea transplant survival at 8 weeks from 33% in the control group to 66% (n=20 in each group).
Blockade of VEGF-C effectively inhibits both the blood and lymphatic vessel growth into the cornea and promotes corneal allograft survival via the reduction of leukocyte trafficking to the lymph node.
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