Abstract 5166: Inhibition of Pro-inflammatory Cytokine Light Reduces Atherosclerotic Lesion Development in Apo E −/− Mice

Abstract

Atherosclerotic plaque typically contains infiltrates of activated macrophages and T cells. We previously showed higher levels of LIGHT in human carotid artery plaque tissue samples of symptomatic (TIA, Stroke) compared to asymptomatic patients. Effects of inhibition of the pro-inflammatory cytokine LIGHT on atherosclerosis development was studied in a rodent model. 30 male apoE −/− mice fed a western diet were treated either with an adenoviral vector, containing the gene sequence for a fusion protein of the extracellular part of the LIGHT receptor molecule TR2 linked with the Fc part of human IgG1 (AdmTR2hIgG), acting as a specific blocking agent against LIGHT (3×10 9 infection units, tail vein injection) (n=10) or an adenoviral vector containing GFP-gene sequence only (AdGFP, sham) (n=10) or mice receiving sodium chloride (untreated group) (n=10). After 8 weeks aortic root was embedded in OCT and serially cryosectioned in 5 μ m intervals. Sections every 75 μ m were stained with Oil RedO, the lesion area was quantified using PC-based image analysis. Inhibition of LIGHT by AdmTR2hIgG markedly reduced atherosclerotic plaque volume (p=0.001) and maximum stenosis (p=0.001) compared to the untreated group or AdGFP treated mice (sham). Analysis of peripheral blood and spleen cells revealed no significant alterations in composition of immune cell compartments or cellular activation status. Immunohistochemistry revealed significant reduction of cellular infiltration by T cells and macrophages as well as T cell- and macrophage density (cell number/lesion area) in atherosclerotic lesions in AdmTR2hIgG compared to untreated/sham mice. Functional blockade of the pro-inflammatory cytokine LIGHT reduced atherosclerotic lesion development in apoE −/− mice without major derangement of peripheral cellular immunity. Our findings suggest a relevant role for LIGHT in atherosclerosis warranting further study of pathogenic mechanisms and therapeutic potential.