title: Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjögren's Syndrome.
abstract: To evaluate the efficacy of topical rapamycin in treating autoimmune dacryoadenitis in a mouse model of Sjögren's syndrome.
  
  
  
  We developed rapamycin in a poly(ethylene glycol)-distearoyl phosphatidylethanolamine (PEG-DSPE) micelle formulation to maintain solubility. Rapamycin or PEG-DSPE eye drops (vehicle) were administered in a well-established Sjögren's syndrome disease model, the male nonobese diabetic (NOD) mice, twice daily for 12 weeks starting at 8 weeks of age. Mouse tear fluid was collected and tear Cathepsin S, a putative tear biomarker for Sjögren's syndrome, was measured. Lacrimal glands were retrieved for histological evaluation, and quantitative real-time PCR of genes associated with Sjögren's syndrome pathogenesis. Tear secretion was measured using phenol red threads, and corneal fluorescein staining was used to assess corneal integrity.
  
  
  
  Lymphocytic infiltration of lacrimal glands from rapamycin-treated mice was significantly (P = 0.0001) reduced by 3.8-fold relative to vehicle-treated mice after 12 weeks of treatment. Rapamycin, but not vehicle, treatment increased tear secretion and decreased corneal fluorescein staining after 12 weeks. In rapamycin-treated mice, Cathepsin S activity was significantly reduced by 3.75-fold in tears (P < 0.0001) and 1.68-fold in lacrimal gland lysates (P = 0.003) relative to vehicle-treated mice. Rapamycin significantly altered the expression of several genes linked to Sjögren's syndrome pathogenesis, including major histocompatibility complex II, TNF-α, IFN-γ, and IL-12a, as well as Akt3, an effector of autophagy.
  
  
  
  Our findings suggest that topical rapamycin reduces autoimmune-mediated lacrimal gland inflammation while improving ocular surface integrity and tear secretion, and thus has potential for treating Sjögren's syndrome-associated dry eye.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Mihir
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Edman
authors.affiliation: Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Reddy Janga
authors.affiliation: Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
authors.forename: Frances
authors.initials: F
authors.lastname: Yarber
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Wannita
authors.initials: W
authors.lastname: Klinngam
authors.affiliation: Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bushman
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Siyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Stan
authors.initials: S
authors.lastname: Louie
authors.affiliation: Anatomic and Clinical Pathology, Los Angeles County + University of Southern California Medical Center, Los Angeles, California, United States.
authors.forename: Arjun
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: Chuanqing
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: MacKay
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States 2Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Hamm-Alvarez
mesh_terms: D000818:Animals; D002403:Cathepsins / Q000096:biosynthesis* / Q000235:genetics; D003228:Conjunctiva / Q000378:metabolism / Q000473:pathology; D003607:Dacryocystitis / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007765:Lacrimal Apparatus / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009883:Ophthalmic Solutions; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage*; D012859:Sjogren's Syndrome / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy; D013666:Tears / Q000378:metabolism*
chemical_list: D007166:Immunosuppressive Agents; D009883:Ophthalmic Solutions; D002403:Cathepsins; C028217:cathepsin S; D020123:Sirolimus