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S. Goyal, S. K. Chauhan, N. Nallasamy, Q. Zhang, R. Dana; Blockade of Prolymphangiogenic VEGF-C Suppresses Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3439.
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Support: Research to prevent blindness NIH EY-19098
Recently we demonstrated that low-grade inflammation associated with dry eye disease (DED) is an inducer of lymphangiogenesis without accompanied hemangiogenesis and that lymphangiogenic specific VEGF-C, VEGF-D and VEGFR-3 are increased in DED corneas. The aim of this study was to determine if blocking prolymphangiogenic factors like VEGF-C would suppress alloimmunity in DED.
The effects of intraperitoneal injections of 400 µg of anti-VEGF-C antibody (treated group) and intraperitoneal normal saline (treated group) were studied in murine dry eyes induced by exposing mice to high-flow desiccated air in the Controlled Environment Chamber (CEC). Age and sex matched mice not placed in CEC served as normal controls. Corneal fluorescein staining was used to evaluate severity of DED. Growth of lymphatic vessels and infiltration of macrophages was evaluated by immunohistochemistry using CD31 (pan-endothelial marker), LYVE -1(lymphatic endothelial marker) and CD11b (monocytes/macrophages marker). In addition, real time PCR was performed to quantify expression of different inflammatory cytokine transcripts in the conjunctiva and lymph nodes, and vascular endothelial growth factors and their receptors (VEGF-A, C, D/ R2, R3) in the cornea.
Blocking VEGF-C led to significant reduction in both lymphatic caliber (P=0.025) and lymphatic area (P=0.006) in the corneas of DED mice. In addition to significantly decreasing (P=0.005) CD11b+ cells, anti-VEGF-C treatment significantly decreased transcript levels of VEGF-C (P=0.002), VEGF-D (P=0.014) and VEGFR-3 (P=0.023) in the corneas of treated group. Significant decrease in expression of inflammatory cytokines in the conjunctiva (IL1- α, IL1-β, IL-6 and IL-17) and lymph nodes (IFN-γ and IL-17) was also seen with anti-VEGF-C treatment.
Treatment with anti-VEGF-C led to significant improvement in DED reflected by decrease in inflammation at the clinical, molecular, and cellular levels.Targeting prolymphangiogenic growth factors or their receptors could inhibit the trafficking of antigen presenting cells to the draining lymph nodes and hence prove to be a potential therapeutic target for dry eye disease.
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