Neutralization of Ocular Surface TNF-α Reduces Ocular Surface and Lacrimal Gland Inflammation Induced by In Vivo Dry Eye

PURPOSE. The purpose of this study was to investigate the effectiveness of tumor necrosis factor (TNF)-alpha blocker for treatment of dry eye (DE)-induced inflammation and determine a more effective method to suppress lacrimal gland inflammation. Efficacy of topical versus systemic administration of TNF-alpha blockers was determined using a murine dry eye (DE) model. METHODS. The TNF-alpha blocker HL036 was developed by modification of the TNF receptor I. Protein purity, binding affinity, and clearance of TNF-alpha was compared with etanercept. Using DE-induced C57BL/6 mice, corneal erosion and goblet cell counts were measured after subcutaneous or topical treatment with etanercept or HL036. Inflammatory cytokines in cornea and lacrimal glands were determined by quantitative RT-PCR and ELISA. RESULTS. HL036 showed TNF-alpha binding affinity comparable to etanercept, as measured by surface plasmon resonance. HL036 concentration was significantly higher in cornea and anterior segment than etanercept and effectively eliminated TNF-alpha on ocular surfaces. Etanercept was preferentially concentrated in the posterior segment. Corneal erosion and goblet cell counts were improved only with topically applied etanercept and HL036. Ocular surface IFN-gamma, IL-6, and IL-21 were significantly decreased by topical HL036. DE-induced lacrimal gland IFN-gamma and IL-6 expression was effectively suppressed by topical etanercept and HL036. CONCLUSIONS. Topical TNF-alpha blockers effectively suppressed lacrimal gland and corneal inflammation by suppressing IFN-gamma, IL-21, and IL-6. Differences in TNF-alpha affinity, clearance, and local concentration of blockers may account for the anti-inflammatory effects in different ocular regions.