Immune Modulation of Atherosclerosis

Abstract

The notion that inflammation plays a role in atherosclerosis dates to separate observations by Virchow and von Rokitansky in the middle of the 19 th century that atherosclerotic blood vessels contained evidence of cellular inflammation. This concept remained stagnant until the 1970s, when Russell Ross demonstrated that monocyte adhesion to the endothelial surface was an early and essential feature of atherosclerosis.1 These observations, coupled with knowledge that modified low-density lipoprotein (LDL) supports foam cell formation and promotes atherosclerosis disease activity,2 focused early investigative efforts on monocytes and macrophages, the foam cell precursors. Indeed, it is clear that neutrophils3 and monocytes enter lesion-prone arterial sites, the latter differentiate into macrophages, and then take up accumulated LDL-cholesterol to form foam cells and early atherosclerotic lesions. Innate immune responses, such as recognition of modified LDL-derived epitopes via macrophage Toll-like receptors, prompts cytokine-mediated recruitment of other inflammatory cells to the lesion4 that, in turn, promote the adaptive immune responses responsible for the chronic inflammation of atherosclerosis. Emerging evidence has helped to refine this paradigm and identify critical events in adaptive immunity that could represent therapeutic opportunities for immune modulation of atherosclerosis. Activated endothelium is characterized by adhesion molecule expression and reduced barrier function that mediate the recruitment of both monocytes5 and T-cells into lesion-prone sites in the arterial wall. With regard to T-cells, histological examination of atherosclerotic lesions demonstrate the presence of both CD4+ T helper (Th) cells, CD8+ cytotoxic T (Tc) cells, and regulatory T cells (Treg) in lesions, although Th cells generally predominate. Lesional T-cells represent a cellular minority …