Abstract

P 222

Effect of integrin alpha 5 inhibition on inflammatory lymphangiogenesis in a murine model of high-risk keratoplasty

Dietrich T.¹, Onderka J.¹, Bock F.¹, Hos D.¹, Zahn G.², Stragies R.², Kruse F. E.¹, Cursiefen C.^1
1Department of Ophthalmology, University of Erlangen-Nürnberg; ²Jerini Pharmaceuticals, Jerini AG, Berlin

Objective: The main risk factor for immune rejections after penetrating keratoplasty (PK) is neovascularization of the cornea. Integrin a5 was recently identified on lymphatic endothelial cells as well as macrophages. Purpose of this study was to analyze whether specific integrin a5 inhibition can reduce lymphangiogenesis (LA) in the context of PK and whether that inhibitory effect is due to direct inhibition of LA or by influencing the recruitment of inflammatory macrophages.
Methods: Inflammatory corneal neovascularization was induced by placing three 11-0 nylon sutures in BalbC mice in a standardized fashion. Mice in the treatment group received integrin a5 inhibiting molecules systemically (JSM6427; 23 mg/kg/d) via subcutaneous osmotic pumps for 14 d (n=20); the control group received vehicle solution (n=20). After this vascularization period, mice were either sacrificed for analysis of LA and macrophage recruitment (n=5 per group) or PK was performed. Corneal grafts from C57Bl/6 mice were used as donors. Mice were sacrificed 6 weeks after PK. For immunohistochemistry, LYVE-1 antibody (specific lymphatic vascular marker) and CD11b as macrophage marker were used on corneal whole mount preparations. The fluorescence microscopic pictures were analyzed morphometrically.
Results: Systemic inhibition of a5 integrin by small molecule antagonists resulted in a significant reduction of lymphatic vessels outgrowth from the limbus both prior to (p<0.001; lymphvascularized area 52.4% vs. control set as 100%) as well as after PK compared to control (p=0.0173; lymphvascularized area 49.8% vs. control 100%). There was no significant reduction of the number of macrophages recruited both prior to (p=0.55) as well as after PK (p=0.4).
Conclusions: Inflammatory LA in the cornea prior to and after PK can be inhibited by blockade of integrin a5. The recruitment of macrophages into the graft was not significantly affected suggesting a direct effect of integrin a5 inhibition on lymphatic endothelial cells.

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