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Effects of Topical Janus Kinase Inhibition on Ocular Surface Inflammation and Immunity

Stevenson, William MD; Sadrai, Zahra MD; Hua, Jing MD; Kodati, Shilpa MD; Huang, Jing-Feng PhD; Chauhan, Sunil K. PhD, DVM; Dana, Reza MD, MPH, MSc

doi: 10.1097/ICO.0000000000000019
Basic Investigation

Purpose: To determine the effects of topical Janus kinase inhibition on ocular surface inflammation and immunity.

Methods: 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.

Results: 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.

Conclusions: Topical ophthalmic tofacitinib, a Janus kinase inhibitor, suppressed ocular surface inflammation and immunity in experimental corneal thermocautery and dry eye disease.

*Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, MA; and

Pfizer, Inc, Medicine Development Group, San Diego, CA.

Reprints: Reza Dana, Schepens Eye Research Institute, 20 Staniford St, Boston, MA 02114 912-0117 (e-mail: reza_dana@meei.harvard.edu).

This research was supported by NIH Grant EY-20889 and Pfizer, Inc. No authors received compensation for the development of this manuscript. J.-F. Huang was an employee of Pfizer, Inc at the time of this study.

The authors have no other funding or conflicts of interest to disclose.

W. Stevenson and Z. Sadrai contributed equally to this manuscript and should be viewed as co–first authors.

Received April 17, 2013

Accepted September 26, 2013

Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.