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

Corneal Staining

mRNA expression levels of IL-1β in the cornea

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