Immunoglobulin treatment suppresses atherosclerosis in apolipoprotein E-deficient mice via the Fc portion

Atherosclerosis is associated with immune activation. Immunoglobulin is used for the treatment of immune-mediated diseases. The mechanisms and importance of the Fc portion of immunoglobulin upon experimental atherosclerosis in apolipoprotein E-deficient mice were examined. Experimental atherosclerosis was induced in mice fed a high-fat diet containing 0.3% cholesterol. Over 8, 12, and 16 wk, on alternate days, mice were treated with an intraperitoneal injection of either 1 g·kg·day of human intact immunoglobulin or F(ab′) fragments of human immunoglobulin. Fatty streak formation and fibrofatty plaques were markedly suppressed in mice that received intact immunoglobulin for 8, 12, and 16 wk. In contrast, atherosclerotic lesions were not ameliorated in mice that received F(ab′)2 fragments. Immunohistochemical analysis revealed that macrophage accumulation in the fatty streak lesions was suppressed in mice received intact immunoglobulin but not in those that received F(ab′)2 fragments. In addition, the cytotoxic activities of splenocytes from immunoglobulin-treated mice, but not from F(ab′)2 fragment-treated mice, were significantly suppressed compared with those from human serum albumin-treated mice. Differences in lesion area did not correlate with any significant alterations in serum lipid levels. Immunoglobulin therapy markedly suppressed atherosclerosis due to Fc receptor-mediated anti-inflammatory and immunomodulating actions. The antiatherosclerotic effects of immunoglobulin may be related to the suppression of cytotoxic activity of atherogenic T cells and the reduction of macrophage accumulation in the lesions.