title: Topical administration of lacritin is a novel therapy for aqueous-deficient dry eye disease.
abstract: OBJECTIVE
  Lacritin is a tear glycoprotein with prosecretory, prosurvival, and mitogenic properties. We examined lacritin levels in the tears of Sjögren's syndrome (SS) patients and explored the therapeutic potential of topical lacritin for the treatment of keratoconjunctivitis sicca.
  
  
  METHODS
  Tears from healthy controls (n = 14) and SS patients (n = 15) were assayed for lacritin using a C-terminal antibody. In a paired-eye study, autoimmune regulator (Aire) knockout (KO) mice (n = 7) were treated three times daily for 21 days with 10 μL of 4 μM lacritin (left eye) or vehicle (PBS) control (right eye). Tear secretion and ocular surface integrity were assessed at baseline and after treatment. Immunohistochemical staining of CD4+ T cells, cytokeratin-10 (K10), and cytokeratin-12 (K12) expression in the cornea and CD4+ T cell infiltration in the lacrimal glands were assessed.
  
  
  RESULTS
  Lacritin monomer (421.8 ± 65.3 ng [SS] vs. 655.8 ± 118.9 ng [controls]; P = 0.05) and C-terminal fragment protein (125 ± 34.1 ng [SS] vs. 399.5 ± 84.3 ng [controls]; P = 0.008) per 100 μL of tear eluate were significantly lower in SS patients. In Aire KO mice treated with lacritin, tear secretion increased by 46% (13.0 ± 3.5 mm vs. 8.9 ± 2.9 mm; P = 0.01) and lissamine green staining score significantly decreased relative to baseline (-0.417 ± 0.06 vs. 0.125 ± 0.07; P = 0.02). Expression of K10 but not K12 in the cornea was significantly decreased in lacritin-treated eyes. Focal CD4+ T cell infiltration of the lacrimal glands was significantly reduced on the lacritin-treated side versus the untreated side.
  
  
  CONCLUSIONS
  Lacritin is significantly reduced in the tears of SS patients. Topically administered lacritin has therapeutic potential for the treatment of aqueous-deficient dry eye disease.
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States.
authors.forename: Trinka
authors.initials: T
authors.lastname: Vijmasi
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States.
authors.forename: Feeling Y T
authors.initials: FY
authors.lastname: Chen
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States.
authors.forename: Suganthalakshmi
authors.initials: S
authors.lastname: Balasubbu
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States.
authors.forename: Marianne
authors.initials: M
authors.lastname: Gallup
authors.affiliation: Department of Integrated Science and Technology, James Madison University, Harrisonburg, Virginia, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: McKown
authors.affiliation: Departments of Cell Biology and Ophthalmology, University of Virginia, Charlottesville, Virginia, United States.
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Laurie
authors.affiliation: Francis I. Proctor Foundation, University of California San Francisco, San Francisco, California, United States Departments of Anatomy and Ophthalmology, University of California San Francisco, San Francisco, California, United States School of Optometry and Vision Science Program, University of California, Berkeley, Berkeley, California, United States.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: McNamara
mesh_terms: D000287:Administration, Topical; D000704:Analysis of Variance; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D016022:Case-Control Studies; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D008934:Mitogens / Q000008:administration & dosage*; D013666:Tears / Q000378:metabolism
chemical_list: D006023:Glycoproteins; C431764:LACRT protein, human; D008934:Mitogens
keywords: Sjögren's syndrome; aqueous-deficient dry eye; lacritin; tears protein; topical therapeutics