June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Topical Rapamycin suppresses lacrimal gland inflammation in a mouse model of Sjögren’s Syndrome
Author Affiliations & Notes
  • Mihir Shah
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Srikanth Reddy Janga
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Maria C Edman
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Zhen Meng
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Jingwen Chen
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Tao Ma
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Wannita Klingamm
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • Chuanqing Ding
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
  • John Andrew MacKay
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
    Biomedical Engineering, University of Southern California, Viterbi School of Engineering, Los Angeles, CA
  • Sarah F Hamm-Alvarez
    Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA
    Research Development, University of Southern California, SC CTSI, Los Angeles, CA
  • Footnotes
    Commercial Relationships Mihir Shah, None; Srikanth Reddy Janga, None; Maria Edman, None; Zhen Meng, None; Jingwen Chen, None; Tao Ma, None; Wannita Klingamm, None; Chuanqing Ding, None; John MacKay, None; Sarah Hamm-Alvarez, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4810. doi:
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      Mihir Shah, Srikanth Reddy Janga, Maria C Edman, Zhen Meng, Jingwen Chen, Tao Ma, Wannita Klingamm, Chuanqing Ding, John Andrew MacKay, Sarah F Hamm-Alvarez; Topical Rapamycin suppresses lacrimal gland inflammation in a mouse model of Sjögren’s Syndrome. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4810.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Current management for Sjögren’s syndrome (SS), a chronic autoimmune disease characterized by lymphocytic infiltration of lacrimal gland (LG) and salivary glands, is symptom alleviation, without addressing its underlying causes. The aim of this study was to evaluate the efficacy of eye drops of a potent immunosuppressant, Rapamycin (Rapa), in suppressing LG inflammation in male non-obese diabetic mouse (NOD), a classic mouse model of SS

Methods: Rapa, a hydrophobic drug, is insoluble in aqueous solutions and hence, was encapsulated using thin film hydration in a simple micelle composed of PEG-DSPE. Rapa and PEG-DSPE were dried by rotary evaporation and re-solubilized in PBS, and the encapsulation efficiency was determined using RP-HPLC. Male NOD mice were administered Rapa micelles or PBS eye drops (control) twice a day, 7 days a week for 12 weeks, starting at 8 wks of age. Mouse tear fluid was collected and investigated for activity of Cathepsin S (CTSS), a putative tear biomarker for SS that has been validated in clinical studies of SS patients and was originally identified in tears of NOD mice. LGs were retrieved for histological evaluation, quantitative PCR of MHC-II and CTSS activity. An unpaired two-tailed student’s t-test was performed to compare the control and treatment groups. Values represent mean ± SEM

Results: 12 wks of Rapa eye drop treatment resulted in a 6.4-fold reduction in LG lymphocytic infiltration in the Rapa (4.9±0.48%) treated group relative to the PBS (31.3±0.82%) treated group (p≤0.0001). CTSS activity was reduced 5.9-fold in tears in the Rapa (52.03±10.8 RFU) vs. PBS treatment group (307.2±75.9 RFU, p=0.0018) and 1.9-fold in LG lysates (Rapa: 3818 ± 454.3, PBS: 7309 ± 525.7 RFU, p=0.0005). This was in accord with a 1.4-fold (p≤0.05) decrease in CTSS mRNA expression in Rapa relative to the PBS-treated mice. There was also a 1.7-fold (p≤0.001) decrease in MHC-II expression, a protein involved in antigen presentation

Conclusions: Eye drop administration has clinical relevance to the treatment of dry eye disease caused by autoimmune inflammation of the LG. Our recent report showed that a 1-week systemic treatment with a nanoparticle formulation of Rapa suppressed LG inflammation. This new report suggests the encouraging finding that when Rapa is administered by topical administration in an eye drop, it can also suppress LG inflammation in the NOD mouse model of SS

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