Integrin Alpha 5 Inhibition Improves Corneal Graft Survival in a Murine Model of High-Risk Keratoplasty

Abstract

Purpose: : Neovascularization of the cornea is the main risk factor for immune rejections after penetrating keratoplasty (PK). We have recently shown that systemic treatment with selective small molecule integrin alpha5 antagonists significantly inhibits lymphangiogenesis in a model of corneal neovascularization. Purpose of this study was to analyze whether selective inhibition of lymphangiogenesis prior to keratoplasty can improve graft survival after high-risk corneal transplantation.

Methods: : Inflammatory corneal neovascularization was induced by placing three 11-0 nylon sutures in 6 week old Balbc mice in a standardized fashion. Mice in the treatment group received integrin alpha 5 inhibiting molecules systemically (JSM6427; 23 mg/kg/d) via subcutaneous osmotic pumps (Alzet® Pumps) for 14 days (n = 23). In the control group, vehicle solution was applied in the same manner (n =30). After this pre-vascularization period, allogenic high-risk PK was performed. We used corneal grafts from 6 week old C57Bl/6 mice as donors. The corneal graft clarity was analyzed every week and quantified by means of an opacity score from 0 (clear graft) to 5 (maximum stromal opacity). As second control group, we performed normal risk keratoplasty without pre-vascularization (n= 30).

Results: : Systemic inhibition of alpha 5 integrin by small molecule antagonists prior to keratoplasty resulted in a statistically significant improvement of graft clarity (p = 0.03) by doubling the number of clear grafts in comparison to the control group of high-risk keratoplasty with a lymph-and hemvascularized host bed. The percentage of clear grafts was not significantly different from the one of the normal risk group.

Keywords: cornea: basic science • immunomodulation/immunoregulation • transplantation