Effects of topical Janus kinase inhibition on ocular surface inflammation and immunity

• Published in: Cornea Vol. 33; no. 2; p. 177
• Main Authors: Stevenson, William, Sadrai, Zahra, Hua, Jing, Kodati, Shilpa, Huang, Jing-Feng, Chauhan, Sunil K, Dana, Reza
• Format: Journal Article
• Language: English
• Published: United States 01.02.2014
• Subjects: Adaptive Immunity - drug effects; Administration, Topical; Animals; CD11b Antigen - genetics; CD11b Antigen - metabolism; Cell Movement; Cytokines - genetics; Cytokines - metabolism; Disease Models, Animal; Dry Eye Syndromes - genetics; Dry Eye Syndromes - immunology; Dry Eye Syndromes - prevention & control; Female; Flow Cytometry; Gene Expression Regulation - physiology; Janus Kinase 3 - antagonists & inhibitors; Keratitis - genetics; Keratitis - immunology; Keratitis - prevention & control; Leukocyte Common Antigens - genetics; Leukocyte Common Antigens - metabolism; Leukocytes - physiology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ophthalmic Solutions; Piperidines - administration & dosage; Protein Kinase Inhibitors - administration & dosage; Pyrimidines - administration & dosage; Pyrroles - administration & dosage; Real-Time Polymerase Chain Reaction; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism
• DOI: 10.1097/ICO.0000000000000019

To determine the effects of topical Janus kinase inhibition on ocular surface inflammation and immunity. Ophthalmic 0.003% tofacitinib (CP-690,550) was administered topically to inhibit Janus kinase activation at the ocular surface. Male BALB/c mice 6 to 8 weeks of age were subjected to corneal thermocautery and randomized to receive tofacitinib, vehicle, or no treatment. Corneas were subsequently excised for fluorescence-activated cell sorting and quantitative real-time reverse transcription polymerase chain reaction. Female C57BL/6 mice 6 to 8 weeks of age were exposed to desiccating stress to induce experimental dry eye disease and randomized to receive tofacitinib, tofacitinib and vehicle, vehicle, or no treatment. Corneal fluorescein staining was performed to evaluate clinical disease severity. The corneas and conjunctivae were harvested for immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction. After corneal thermocautery, it was found that tofacitinib treatment decreased the corneal infiltration of CD45+, Gr-1+, and CD11b+ cells on days 1 and 3. Transcripts encoding interleukin (IL)-1β and IL-6 were significantly decreased by tofacitinib treatment at post-thermocautery day 3. In experimental dry eye disease, tofacitinib treatment twice per day significantly decreased corneal fluorescein staining on days 12 and 15. The corneal infiltration of CD11b+ cells was significantly decreased by tofacitinib treatment twice per day. Tofacitinib treatment twice per day significantly increased the corneal expression of IL-1RA, and significantly decreased the corneal expression of tumor necrosis factor and IL-23. Further, tofacitinib treatment twice per day significantly decreased the conjunctival expression of IL-17A and significantly increased the conjunctival expression of FoxP3. Topical ophthalmic tofacitinib, a Janus kinase inhibitor, suppressed ocular surface inflammation and immunity in experimental corneal thermocautery and dry eye disease.