2009 OMIG, Abstract 22

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Therapeutic Eefficacy of Topical Tlockade of Interleukin-1 in Murine Dry Eye Disease.
A. Okanobo, M. Dastjerdi, S. Chauhan, N. Nallasamy, Z. Sadrai, R. Dana
Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts  

Purpose: Dry eye disease (DED) is a complex inflammatory disorder of the ocular surface affecting tens of millions of people worldwide. The proinflammatory cytokine interleukin-1 (IL-1) has been shown to be critically involved in the pathogenesis of several immune and inflammatory conditions, but its role in DED remains unknown. The purpose of this study was to evaluate the efficacy of topical blockade of IL-1 using its natural antagonist, IL-1 receptor antagonist (IL-1Ra), in ameliorating DED.
Methods: Dry eye was induced in female C57BL/6 mice by exposing them to a desiccating controlled environment chamber. Formulations of (i) 5% IL-1Ra in carboxy-methyl-cellulose (CMC), (ii) 0.05% CsA (Allergan), (iii) nonpreserved 1% methylprednisolone or (iv) vehicle (CMC alone) were topically applied to different groups of DED mice (n=8 eyes/group) 3x/daily. DED was scored by corneal fluorescein staining (CFS). Immunohistochemistry and real-time PCR were performed to quantify CD11b+ infiltration and lymphatics, and IL-1β expression, respectively.
Results: DED mice which received topical IL-1Ra, methylprednisolone and Restasis showed a significant decrease in the CFS compared to those receiving vehicle alone [mean ± SEM (60% ± 3.8, 55% ± 3.7, 34% ± 5.3  vs. 13% ± 2.0; P<0.003)], respectively, with IL-1Ra and methylprednisolone showing a significantly greater efficacy than CsA. Therapy with IL-1Ra and methylprednisolone, compared with the vehicle group, significantly decreased the total number of CD11b+ cells in the cornea (163.3 ± 9.6, 165.1 ± 8.2 vs. 236.6 ± 18.1; P<0.003), respectively. The IL-1Ra and methylprednisolone treated eyes also showed a 2-3 fold (P<0.04) decrease in the ingrowth of corneal lymphatics and a 5-6 fold (P<0.03) decrease in the corneal expression of IL-1β mRNA compared to those receiving vehicle alone.
Conclusion: The reversal of clinical signs and underlying inflammatory changes by topical IL-1Ra treatment clearly suggests that topical IL-1Ra could be an effective therapeutic modality for the treatment of DED. IL-1Ra may also be considered as an alternative to topical steroid therapies, which are fraught with numerous side effects.
Financial support: Research to Prevent Blindness and NIH K24EY019098
Disclosure Code: P