sar-1118 and Inflammation

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.

Topics: Administration, Topical; Clinical Decision-Making; Cyclosporine; Dry Eye Syndromes; Goblet Cells; Homeostasis; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammation; Integrins; Intercellular Adhesion Molecule-1; Lacrimal Apparatus; Lymphocyte Function-Associated Antigen-1; Phenylalanine; Steroids; Sulfones; T-Lymphocytes; Tears

Increased interferon gamma (IFN-γ) expression in dry eye causes ocular surface epithelial disease termed keratoconjunctivitis sicca (KCS). The purpose of this study was to investigated the effects of the LFA-1 antagonist, lifitegrast, in a mouse desiccating stress (DS) dry eye model that develops KCS similar to Sjögren syndrome.. Mice were treated with vehicle or lifitegrast twice daily for 5 days and expression of Th1 family genes (IFN-γ, CXCL9, and CXCL11) was evaluated by real-time polymerase chain reaction. Cornea barrier function was assessed by Oregon Green dextran staining and goblet cell number and area were measured.. Compared to the vehicle-treated group, the lifitegrast-treated group had significantly lower expression of Th1 family genes, less corneal barrier disruption, and greater conjunctival goblet cell density/area.. These findings indicate that lifitegrast inhibits DS-induced IFN-γ expression and KCS. This suggests that ICAM-LFA-1 signaling is involved with generation of Th1 inflammation in KCS.

Topics: Animals; Chemokine CXCL11; Chemokine CXCL9; Dry Eye Syndromes; Female; Inflammation; Interferon-gamma; Keratoconjunctivitis Sicca; Mice; Mice, Inbred C57BL; Ophthalmic Solutions; Phenylalanine; Sulfones; Th1 Cells

Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells. Lifitegrast is a T-cell integrin antagonist designed to mimic ICAM-1, thus blocking the interaction of LFA-1 and ICAM-1. Lifitegrast enters the systemic circulation to a limited extent thus reducing the likelihood of unwanted systemic reactions. Clinical trials in over 2,500 subjects with dry eye disease have shown that 5.0% lifitegrast given by ocular instillation causes a significant reduction in objective and subjective signs and symptoms of the disease. These beneficial effects are associated with a relatively low incidence of unwanted effects, almost all local in nature. In light of these findings, lifitegrast was approved by the Food and Drug Administration (FDA) in 2016 for the treatment of dry eye disease, the first drug with this mechanism of action to be so approved.

Topics: Anti-Inflammatory Agents; Clinical Studies as Topic; Drug Evaluation, Preclinical; Dry Eye Syndromes; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Ophthalmic Solutions; Phenylalanine; Sulfones; T-Lymphocytes

Sterile corneal infiltrates can cause pain, blurred vision, and ocular discomfort in silicone hydrogel contact-lens users. The current study investigates the potential for the synthetic lymphocyte functional antigen-1 (LFA-1) antagonist lifitegrast (SAR 1118) to block corneal inflammation using a murine model.. The role of LFA-1 (CD11a/CD18) was examined either in CD18(-/-) mice, by intraperitoneal injection of anti-CD11a, or by topical application of lifitegrast. Corneal inflammation was induced by epithelial abrasion and exposure to either tobramycin-killed Pseudomonas aeruginosa or Staphylococcus aureus in the presence of a 2-mm-diameter punch from a silicone hydrogel contact lens. After 24 h, corneal thickness and haze were examined by in vivo confocal microscopy, and neutrophil recruitment to the corneal stroma was detected by immunohistochemistry.. Neutrophil recruitment to the corneal stroma and development of stromal haze were significantly impaired in CD18(-/-) mice or after injection of anti-CD11a. Topical lifitegrast also inhibited P. aeruginosa- and S. aureus-induced inflammation, with the optimal application being a 1% solution applied either 2 or 3 times prior.. As LFA-1-dependent neutrophil recruitment to the corneal stroma can be blocked by topical lifitegrast, this reagent could be used in combination with antibiotics to prevent leukocyte infiltration to the corneal stroma in association with contact-lens wear.

Topics: Animals; CD11a Antigen; CD18 Antigens; Contact Lenses; Cornea; Corneal Stroma; Disease Models, Animal; Eye Infections, Bacterial; Inflammation; Lymphocyte Function-Associated Antigen-1; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Confocal; Neutrophil Infiltration; Phenylalanine; Pseudomonas aeruginosa; Pseudomonas Infections; Staphylococcal Infections; Staphylococcus aureus; Sulfones