PDE4 Inhibition Suppresses IL-17–Associated Immunity in Dry Eye Disease

Abstract

Topical cilomilast suppresses the generation of IL-17-associated immunity in experimental DED.

T helper cytokines in dry eye disease

“…Pathogenic CD4 cells that infiltrate the ocular surface tissues express receptors to these ligands (de Paiva et al, 2009; Yoon et al, 2007; Yoon et al, 2010; Dohlman TH et al, 2013). It has also been shown that manipulation of afferent (migration of dendritic cells from the ocular surface to the regional lymph nodes) or efferent (migration of differentiated CD4+ T cells from the nodes to the cornea and conjunctiva) can ameliorate development of dry eye disease (Coursey et al, 2012; Goyal et al, 2009; Lee et al, 2011; Sadrai et al, 2012; Schaumburg et al, 2011) indicating that therapeutic strategies that interfere with various points in this immune circle may have clinical significance. As a matter of fact, cyclosporine A 0.01 % emulsion, the only FDA-approved drug to treat dry-eye disease has been shown to modulate several arms of the immune response by decreasing human leukocyte class II antigen (HLA-DR) expression in conjunctiva of dry eye patients (Baudouin et al, 2002; Brignole et al, 2000; Brignole et al, 2001) and decreasing expression of IL-17A and IFN-γ in conjunctiva of animals after desiccating stress (de Paiva et al, 2009).…”

The CCR6/CCL20 Axis Mediates Th17 Cell Migration to the Ocular Surface in Dry Eye Disease

“…6,20 Mice were housed in a low-humidity (relative humidity: <20%) controlled environment chamber (CEC) with constant air flow (15 L/min) for 12 days and received 5 mg/mL subcutaneous scopolamine hydrobromide (Sigma-Aldrich, St. Louis, MO) injections three times per day. Topical atropine sulfate (1%; Bausch & Lomb, Rochester, NY) was administered twice per day on days 1 and 2 to enhance anticholinergic effects.…”

“…4 Antigen-presenting cells from the inflamed ocular surface home to the draining lymph nodes, where they prime naïve T cells to differentiate into pathogenic T effectors, including interleukin-17 secreting CD4þ T cells (Th17). These Th17 cells then migrate from the lymph nodes 5 to the conjunctiva, 6 where they propagate inflammation and cause tissue damage by secreting potent inflammatory cytokines. 7 Although several studies now implicate Th17 cells as the dominant pathogenic effectors in DED, 5,7,8 the specific mechanisms by which they migrate to the ocular surface are unknown.…”

“…To validate our hypothesis, we systematically explored a well-characterized murine model of dry eye. 6,20 We evaluated the generation of Th17 cells and their expression of the chemokine receptor CCR6, as well as the presence of CCL20 at the ocular surface. Furthermore, we used local, in vivo neutralization of CCL20 to demonstrate the functional releCopyright 2013 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 vance of the CCR6/CCL20 axis in mediating Th17 cell migration and DED pathogenesis.…”

The eye: a window of opportunity in rheumatoid arthritis?

“…Treatment with phosphodiesterase type4 can reduce T H 17cellmediated ocular surface inflammation in an experimental animal model of dry eye. 88 To antagonize leukocyte trafficking, a small molecule inhibitor of LFA1 is being evaluated in dry eye in a phase III study. 89 Targeting signalling pathways is another promising strategy; for example, cytokine signal ling can be suppressed by Janus kinase (JAK) inhibitors.…”