title: Effects of topical Janus kinase inhibition on ocular surface inflammation and immunity.
abstract: OBJECTIVE
  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.
authors.affiliation: *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.
authors.forename: William
authors.initials: W
authors.lastname: Stevenson
authors.forename: Zahra
authors.initials: Z
authors.lastname: Sadrai
authors.forename: Jing
authors.initials: J
authors.lastname: Hua
authors.forename: Shilpa
authors.initials: S
authors.lastname: Kodati
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Huang
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Chauhan
authors.forename: Reza
authors.initials: R
authors.lastname: Dana
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000287:Administration, Topical; D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D007634:Keratitis / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009883:Ophthalmic Solutions; D010880:Piperidines / Q000008:administration & dosage*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011758:Pyrroles / Q000008:administration & dosage*; D060888:Real-Time Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; C503133:Gr-1 protein, mouse; D009883:Ophthalmic Solutions; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D019707:Receptors, Chemokine; C479163:tofacitinib; D053616:Janus Kinase 3; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse