Leukocyte Function-Associated Antigen-1 (LFA-1) Antagonist Lifitegrast Prevents Corneal Recruitment of Effector T cells (Th1) by Modulating CXCR3 and CCR4 expression During Dry Eye Disease (DED)

Abstract

Purpose : The interaction of ICAM-1/LFA-1 is essential for T cell activation and migration. lntravascular ICAM-1 has been shown to be upregulated during corneal inflammation, such as in dry eye disease (DED). The purpose of this study was to assess if LFA-1 antagonist Lifitegrast can reduce CD4⁺ T cell migration to the cornea by modulating the expression of chemokine receptors during DED

Methods : DED was induced in 6–8 week-old mice 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. Fifteen days later, DED severity was assessed with corneal fluorescein score (CFS) and T cells were quantified by flow cytometry (FC) of corneal single cells for the cytokines IFN-γ (Th1) or IL-17A (Th17). Expression of chemokine receptors on T cells from local draining lymph nodes (dLNs) were assessed by qRT-PCR and FC. CD4⁺ T cells from DED mice treated with Lifitegrast or NS were sorted and adoptively transferred to RAG knockout (KO) mice. Five days later, DED severity was assessed and T cells were quantified in pooled corneas and dLNs by FC

Results : CFS and tear secretion were significantly increased at day 15 in DED mice treated with Lifitegrast, compared to DED mice treated with NS (p <0.001). Lifitegrast treatment resulted in reduction of CD4⁺ T cell recruitment (Th1) to the cornea by FC(P<0.05) with reduction of corneal IFN-γ and TNF-α compared to DED mice treated with NS. CD4⁺ T cells from dLNs showed reduction on the expression of chemokine receptors CXCR3 and CCR4 by FC in DED-Lifitegrast vs. NS-treated controls mice (p<0.05). Interestingly, adoptive transfer of CD4⁺ T cells from DED mice treated with Lifitegrast resulted in significant reduction of CFS and improved tear secretion (p<0.05) with reduction of T cells (Th1) recruitment into the cornea (17% vs. 44%) but no changes in the dLN compared to NS-treated controls

Conclusions : Lifitegrast treatment reduces CFS and improves tear secretion in DED mice, and resulted in significant reduction in corneal effector Th1 cell recruitment and reduction in pro-inflammatory cytokines. Lifitegrast treatment may mediate DED by inhibiting corneal T cell migration through the modulation of CXCR3 and CCR4 expression on CD4⁺ T cells in dLNs

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.