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Gustavo Ortiz, Victor G. Sendra, Arsia Jamali, Pedram Hamrah; Mechanisms of Action of the Leukocyte Function-Associated Antigen-1 (LFA-1) Antagonist Lifitegrast in Dry Eye Disease (DED). Invest. Ophthalmol. Vis. Sci. 2018;59(9):3315.
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The interaction of ICAM-1/LFA-1 is essential for T cell activation and migration. Intravascular ICAM-1 has been shown to be upregulated during corneal inflammation, such as in DED. The purpose of this study was to assess if LFA-1 antagonist Lifitegrastcan modulate T cell migration to the ocular surface andmediate T cell changes in draining lymph nodes (dLNs) during DED
DED was induced in 6-8 week old wild-type or Tred mice (RFP-expressing T cells) by exposure to the controlled environment chamber and subcutaneous injections of scopolamine. Mice were treated with topical Lifitegrast (or normal saline [NS] control) 3 times daily. DED severity was assessed with corneal fluorescein score (CFS). Corneal and conjunctival T cells were quantified by flow cytometry of single cell suspensions. Conjunctival Tred cell density was also quantified using intravital multiphoton microscopy (IV-MPM). Tred cells were quantified in tear lavages using epi-florescent microscopy. mRNA levels of IL-17, IL-6, and FoxP3 were measured in tear samples using qRT-PCR. Submandibular dLNs were assessed for density of T helper (Th)1, Th17 and T regulatory (Treg) cells by flow cytometry
CFS was significantly reduced at days 10 and 15 in DED mice treated with Lifitegrast, compared to DED mice treated with NS (p <0.001). Lifitegrast did not result in changes in corneal and conjunctival T cells by flow cytometry (P>0.05). However, on day 15 after DED induction, the density of Tred cells in focal areas of the conjunctiva were reduced in the DED-Lifitegrast vs. DED-NS treated mice (p=0.021) as shown by IV-MPM. The density of T cells did not change with any treatment group in the tears (P>0.05). However, while IL-17 and IL-6 mRNA levels were decreased, FoxP3 mRNA level was increased in tears of DED-Lifitegrast vs. NS-treated controls (p<0.05). Interestingly, Lifitegrast treatment resulted in significantly reduced density of Th1 cells at day 10 following DED induction compared with DED-NS treated group in dLNs (p<0.05)
Lifitegrast treatment reduces CFS in mice with DED. While Lifitegrast did not result in significant changes in T cell density in the cornea, conjunctiva and tears, focal conjunctival T cell decrease and reduction in pro-inflammatory cytokines in tears were observed. Lifitegrast may be modulating DED by inhibiting T cell sensitization and phenotype in dLNs
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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