LFA-1/ICAM-1 Interaction as a Therapeutic Target in Dry Eye Disease

Abstract

Dry eye disease (DED) is a common ocular disorder associated with inflammation of the lacrimal gland and ocular surface. The interaction of the integrin lymphocyte function-associated antigen-1 (LFA-1) with its cognate ligand intercellular adhesion molecule-1 (ICAM-1) is known to have important roles in the interaction of a variety of cells involved in immune responses and inflammation, including those prominent in ocular surface inflammation. Lifitegrast, an LFA-1 antagonist that blocks binding of ICAM-1 to LFA-1, has recently been approved in the United States for the treatment of signs and symptoms of DED. In this review, we evaluate research findings to explore the potential role of LFA-1/ICAM-1 interaction in the pathophysiology of DED, and the evidence supporting LFA-1/ICAM-1 interaction as a rational therapeutic target in DED. The results of our review suggest that LFA-1/ICAM-1 interaction may play important roles in the cell-mediated immune response and inflammation associated with DED, including facilitating the homing of dendritic cells to the lymph nodes, interaction of dendritic cells with T cells and subsequent T cell activation/differentiation, migration of activated CD4+ T cells from the lymph nodes to the ocular surface, reactivation of T cells by resident antigen-presenting cells at the ocular surface, and recruitment and retention of LFA-1-expressing T cells in the conjunctival epithelium. Based on the available evidence, inhibition of LFA-1/ICAM-1 interaction represents a rational targeted approach in treating DED. Notably, inhibition of LFA-1/ICAM-1 binding with lifitegrast offers a novel approach to reducing ocular surface inflammation in this condition.

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

“…[107] This interaction is essential to a number of T-cell interactions such as T-cell activation by antigen-presenting cells and strong adhesion to the endothelial cells during extravasation. [107,139] Due to the role of LFA-1 in T-cell function, an antagonist of LFA-1 was investigated for the treatment of DED. [139] In a desiccating stress murine model, a reduction of ocular surface inflammation was observed.…”

“…[107,139] Due to the role of LFA-1 in T-cell function, an antagonist of LFA-1 was investigated for the treatment of DED. [139] In a desiccating stress murine model, a reduction of ocular surface inflammation was observed. [140] Furthermore, the drug was assessed in a clinical trial of 588 masked, randomized subjects who either were given a placebo (control) or received topically administered Lifitegrast (5.0%) (Twice a day) for a period of 84 days.…”

“…[141] Lifitegrast ophthalmic solution is currently approved by the FDA and is commercially marketed as Xiidra© (Shire Pharmaceuticals, Lexington, MA, USA). [139] …”

Omega‐3 supplementation is neuroprotective to corneal nerves in dry eye disease: a pilot study

“…Given the role of inflammation in its pathogenesis, anti‐inflammatory agents are often prescribed to manage the clinical signs and symptoms of DED. In addition to topical corticosteroids and cyclosporine‐A, a novel immuno‐modulatory agent (lifitegrast) that reduces T‐lymphocyte mediated inflammation, has recently been approved by the United States of America Federal Drug Administration, for the therapeutic treatment of DED . A further therapeutic option involves omega‐3 (ω‐3) essential fatty acid (EFA) supplementation.…”

Clinical utility of cyclosporine (CsA) ophthalmic emulsion 0.05% for symptomatic relief in people with chronic dry eye: a review of the literature

“…Given the recent FDA approval of lifitegrast ophthalmic solution 5% (Xiidra ® , Shire, Lexington, MA, USA), revisiting the literature on CsA is timely. Although the mechanisms of action are different, both CsA and lifitegrast address the underlying inflammatory process in DED 1,3…”