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Y. Liu, J. Cao, W. Xiao, E. M. Koehler-Stec, J. S. Rudge, G. D. Yancopoulos, S. W. Wiegand; Systemic Administration of a Murine Interleukin-1 (mIL-1) Trap Inhibits Suture-Induced Corneal Angiogenesis in the Mouse. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1492.
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We have previously reported that systemic administration of an adenoviral encoding a murine IL-1 Trap (a chimeric protein comprising the ligand binding domains of murine IL-1R1 and IL-1RacP and mouse Fc) suppressed corneal neovascularization (NV) and inflammation (Cao et al. IOVS 2003; 44: E-Abstract 823). The present study evaluates effects of systemic administration of mIL-1 Trap protein on suture induced corneal injury, and compares its effects with anakinra, a recombinant human interleukin 1 receptor antagonist (IL-1RA).
Adult male C57/BL6 mice were anesthetized with ketamine (120 mg/kg) and xylazine (5 mg/kg). Corneal NV was induced by intrastromal placement of three nylon sutures. mIL-1 Trap was administered subcutaneously (s.c.) at 50, 100, and 200 mg/kg respectively, beginning with a single pretreatment before injury (Day -1) followed by treatment immediately after injury (Day 0) and once every other day thereafter (Day 2, 4, 6 and 8). Control animals received mFc (17 mg/kg) following the same schedule. Mice treated with anakinra received daily s.c. injections of 300 mg/kg or 500 mg/kg, from Day -1 to Day 8. Nine days following injury, the corneal vasculature was labeled by intravenous injection of fluorescein conjugated lycopersicon esculentum lectin, and the extent of NV was evaluated post-mortem in corneal flat-mounts. Photoshop CS2, Fovea 4.0, and Scion Image program were used to measure the length of corneal neovessels. Infiltration of leukocytes was evaluated in cross-sections stained with H&E. Serum levels of mIL-1 Trap were determined by ELISA on day 9.
Subcutaneous administration of mIL-1 Trap significantly suppressed corneal NV at all doses tested, with treatment at 100mg/kg once every other day resulting in almost completely inhibition of corneal NV. Daily administration of anakinra at 500 mg/kg resulted in a comparable reduction in neovascularization, while daily administration of anakinra at 300 mg/kg resulted in a more modest reduction in corneal NV that was not statistically significant.
This study demonstrates that systemic administration of IL-1 blockers can effectively inhibit corneal neovascularization following suture injury. Maximal effects were obtained at lower doses, and with less frequent dosing with a chimeric, receptor based murine IL-1 Trap compared to anakinra, a recombinant IL-1 receptor antagonist.
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