OBJECTIVE: To study the effect of topical application of very late antigen 4 (VLA-4) small-molecule antagonist (anti-VLA-4 sm) in a mouse model of dry eye disease. METHODS: Anti-VLA-4 sm (or control vehicle) was applied topically to mice placed in a controlled-environment chamber. Corneal fluorescein staining and conjunctival T-cell enumeration were performed in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva. RESULTS: Dry eye syndrome induced increased corneal fluorescein staining, corneal and conjunctival tumor necrosis factor alpha messenger RNA expression, and T-cell infiltration into the conjunctiva. Very late antigen 4 blockade significantly decreased corneal fluorescein staining compared with the untreated dry eye disease and control vehicle-treated groups (P < .001 and P = .02, respectively). In addition, VLA-4 blockade was associated with a significant decrease in conjunctival T-cell numbers (P < .001 vs control vehicle-treated group) and tumor necrosis factor-alpha transcript levels in the cornea (P = .04 vs control vehicle-treated group) and conjunctiva (P = .048 vs control vehicle-treated group). CONCLUSION: Application of topical anti-VLA-4 sm led to a significant decrease in dry eye signs and suppression of inflammatory changes at the cellular and molecular levels. CLINICAL RELEVANCE: Topical blockade of VLA-4 may be a novel therapeutic approach to treat the clinical signs and inflammatory changes accompanying dry eye disease.
OBJECTIVE: To study the effect of topical application of very late antigen 4 (VLA-4) small-molecule antagonist (anti-VLA-4 sm) in a mouse model of dry eye disease. METHODS: Anti-VLA-4 sm (or control vehicle) was applied topically to mice placed in a controlled-environment chamber. Cornealfluorescein staining and conjunctival T-cell enumeration were performed in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva. RESULTS:Dry eye syndrome induced increased cornealfluorescein staining, corneal and conjunctival tumor necrosis factor alpha messenger RNA expression, and T-cell infiltration into the conjunctiva. Very late antigen 4 blockade significantly decreased cornealfluorescein staining compared with the untreated dry eye disease and control vehicle-treated groups (P < .001 and P = .02, respectively). In addition, VLA-4 blockade was associated with a significant decrease in conjunctival T-cell numbers (P < .001 vs control vehicle-treated group) and tumor necrosis factor-alpha transcript levels in the cornea (P = .04 vs control vehicle-treated group) and conjunctiva (P = .048 vs control vehicle-treated group). CONCLUSION: Application of topical anti-VLA-4 sm led to a significant decrease in dry eye signs and suppression of inflammatory changes at the cellular and molecular levels. CLINICAL RELEVANCE: Topical blockade of VLA-4 may be a novel therapeutic approach to treat the clinical signs and inflammatory changes accompanying dry eye disease.
Authors: Michael E Stern; Chris S Schaumburg; Karyn F Siemasko; Jianping Gao; Larry A Wheeler; Devin A Grupe; Cintia S De Paiva; Virginia L Calder; Margarita Calonge; Jerry Y Niederkorn; Stephen C Pflugfelder Journal: Invest Ophthalmol Vis Sci Date: 2012-04-24 Impact factor: 4.799