new antiinflammatory strategy to treat murine dry-eye disease andré okanobo, md, mohammad...
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New Antiinflammatory Strategy to Treat Murine Dry-Eye DiseaseAndré Okanobo, MD, Mohammad Dastjerdi, MD, Sunil Chauhan, DVM, PhD, Nambi Nallasamy, BS, Zahra Sadrai, MD, Reza Dana, MD, MPH, MSc. Schepens Eye Research Institute,Harvard Medical School, Boston, MA
Financial Disclosures :The Schepens Eye Research Institute and Mass. Eye and Ear Infirmary hold rights to the intellectual property for the use of IL-1 blockade in ocular surface disease.Financial support: Prevent Blindness America and NIH K24EY019098
Inflammation and Dry Eye• Dry eye was originally considered to be simply a lack,
or diminishment, of tear production• We now know that inflammation plays a critical role
in the pathophysiology• This is supported by clinical data using anti-
inflammatory therapies which lead to significant amelioration of the signs and symptoms of DED
IL-1 and IL-1Receptor Are Upregulated in Dry Eye
Normal
40x
40x
Dry Eye
40x
IL-1R Expression; Cross-Section Cornea Epifluorescent Microscope
40xEP EP
AC
ACAC
Propose• Given that IL-1–mediated mechanisms play a
critical role in corneal inflammation, we propose that local blockade of IL-1 may offer a novel approach to the management of dry eye disease
Interleukin-1 (IL-1)Proinflammatory forms
• IL-1α• IL-1β
Anti-inflammatory form
• IL-1 receptor antagonist (IL-1Ra)
IL-1AcP
IL-1R
IL-1
SignalTransduction
Kinase, Phosphatase, etc.
IL-1AcPIL-1R IL-1
IL-1Ra
Induction of Dry Eye Disease• Controlled Environment Chamber
– humidity below 25%– constant temperature of 21-23ºC– airflow of 15 L/minute
• Topical atropine and SC scopolamine
Barabino S, et al. The controlled environment chamber: a new mouse model of dry eye. Invest Ophthalmol Vis Sci. 2005;46(8):2766-2771.
Topical formulation and treatment regiment
0 1 2 3 4 5 6 7 8 9 10
Induction of Dry Eye Treatment
CFS CFS
Control Environment Chamber
CFS
DAY
CFS Euthanized
Groups (n=6 eye)
1.IL-1Ra
2.CsA
3.Methylprednisolone
4. Vehicle (1% carboxymethylcellulose)
5. Untreated (no eye drops)
3µl (3x/day)
CFS: Corneal Fluorescein Staining
•Formulation prepared by MEEI pharmacy •Masked Fashion
Enumeration of macrophages in the cornea
Untreated (Dry eye) CMC (Vehicle)
0.05% CsA 5% IL - 1Ra 1% Methylprednisolone
Normal
IL-1Ra inhibits lymphangiogenesis in dry eye
Dry EyeNormal
LYVE-1(Lymphatics Vessels) / CD31(Blood Vessels)
IL-1Ra 5%
Conclusion• IL-1Ra ameliorates dry eye disease comparable to
methylprednisolone– Signs: CFS scores were significantly improved
• Our data suggests that this is due to the marked inhibition of corneal inflammation:– Down regulated levels of IL-1β mRNA– Reduced infiltration of macrophages– Inhibition of lymphangiogenesis
• Thus the use of topical IL-1Ra appears to be a promising therapeutic modality to dry eye disease and possibly in other inflammatory conditions of the cornea and ocular surface