A Novel Modulator of the IL-1 Receptor Prevents Development of Oxygen-Induced Retinopathy

Abstract

Purpose: : Retinopathy of prematurity (ROP), is associated with generation of inflammatory mediators. In this context, interleukin-1β (IL-1β) is an established prominent cytokine. IL-1 receptor antagonist (Kineret) is a large protein and the only clinically available inhibitor of IL-1β. Our laboratory developed a novel small allosteric modulator of IL-1 receptor, labelled 101.10 (Quiniou et al, J Immunol, 2008). We investigated whether inhibiting the actions of IL-1β using 101.10 prevented the vaso-obliteration and pathological neovascularization associated with oxygen-induced retinopathy (OIR).

Methods: : Vaso-obliteration was induced in Sprague-Dawley rat pups maintained in 80% O₂ from postnatal days (P)5 to P10. IL-1β was measured in retinas. 101.10’s ability to curb vaso-obliteration was tested on animals exposed to O₂ from P5-P10; while its effects on pre-retinal neovascularization was tested on newborn rats subjected to OIR model (cycling O₂ during 14 days [50% and 10%] followed by room air until P18). Animals received 101.10 or vehicle by intraperitoneal (3mg/kg/day) or oral administration (5mg/kg/day) from birth to sacrifice. Neovascularization was evaluated in retinal flat-mounts stained with lectin.

Results: : Retinas from pups exposed to 80% O₂ exhibited increased levels of IL-1β at 12, 24 and 48 h post-O₂ exposure. Antagonism of IL-1 receptor using intravitreal injection of 101.10 significantly attenuated vaso-obliteration. Intraperitoneal administration of 101.10 efficiently decreased pathological neovascularization compared to vehicle treatment, protection was generally superior to that observed with Kineret. Moreover, orally administered 101.10 was also found to be effective in preventing vaso-obliteration and aberrant pre-retinal neovascularization.

Conclusions: : Results suggest that the major pro-inflammatory cytokine IL-1β is implicated in the pathogenesis of ROP. 101.10, a potent small molecule inhibitor of IL-RI, is a promising therapeutic candidate to help preserve vascular beds and decrease the detrimental angiogenesis associated with ischemic retinopathies.

Keywords: retinopathy of prematurity • inflammation • cytokines/chemokines