A Novel Cell Adhesion Inhibitor, K-7174, Reduces Lymphocyte Infiltration and Increases Tear Production in Sjögren's Syndrome Model Mouse

Abstract

Abstract: : Purpose: To investigate the effect of a novel cell adhesion inhibitor, K-7174, for the improvement of dry eye in Sjögren’s model mouse. Methods: A total of 30 NFS/sld thymectomized mice, 4 weeks after birth, were treated by oral administration (N=15, vehicle, 10m/kg and 30mg/kg) or topical application (N=15, vehicle, 0.8mg/ml, and 2.4mg/ml) of K-7174 for 10 weeks. Tear secretion was measured by cotton thread and lymphocyte infiltration in the lacrimal glands were graded. Gene expression of lacrimal glands, with and without treatment, were assayed by gene-chip analysis (Affymetrix). Results: Tear secretion increased to 0.175 +/- 0.062 (10mg/kg) and 0.198 +/- 0.039 (30mg/kg) in oral administered groups compared to 0.092 +/- 0.030 mm/min/g (vehicle). Similar results were obtained in the topical treatment group. Lymphocyte infiltration grades decreased to 0.63 +/- 0.31 (10mg/kg) and 0.0 +/- 0.0 (30mg/kg) compared to 3.71 +/- 0.41 (vehicle). Similar results were obtained in topical administered groups (0.6+/-0.48 in 2.4mg/ml, 0.6 +/- 0.48 in 0.8mg/ml and 2.6+/- 0.9 in vehicle). Fractalkine, a newly discovered lymphocyte trafficking chemokine, was found to be suppressed dramatically in the lacrimal gland of treated mice among the 11 suppressed genes. Conclusion: Both systemic and topical application of K-7174 increases tear secretion and decreases lymphocyte infiltration of lacrimal glands in NFS/sld thymectomized mice. K-7174 could possibly be a new drug for the control of inflammation of Sjögren's syndrome and Fractalkine may one of the target molecules in this treatment mechanism.

Keywords: conjunctiva • cornea: epithelium • lacrimal gland