Non-Fas(CD95/APO1)-mediated apoptosis of activated T cells inhibits the development of atherosclerosis.

Atherosclerosis is a chronic systemic inflammatory disease. The innate and adaptive immune response might be involved in atherogenesis. Methotrexate (MTX) induces apoptosis of activated T cells by a CD95-independent pathway. The aim of this study was to analyse the effect of immunomodulation by MTX in the development of early atherosclerotic vascular lesions in an animal model. Four-week old male C57BL6 LDL-receptor-deficient mice were fed a diet rich in saturated fat (82%) and cholesterol (2.8%). Thirty animals were given a weekly intramuscular injection of MTX, establishing three subgroups: 10, 30 and 50 mg/kg. Ten further mice were used as an immunocompetent control group. Aortic thickening was significantly inhibited in all MTX-treated groups compared with the control group at 30 days (0.46 ± 0.003 mm(2) in the control group vs 0.31 ± 0.002, 0.14 ± 0.009 and 0.16 ± 0.006 mm(2) in the low-, intermediate- and high-dose group, respectively; P = 0.01) and at 60 days. The aortic lumen/total area ratio was also increased in the MTX-treated groups (0.82 ± 0.06 in the control group vs 0.88 ± 0.07, 0.86 ± 0.05 and 0.88 ± 0.04, respectively; P = 0.02). Immunosuppression by MTX inhibits the development of atherosclerotic lesions in arterial vessels in mice, which highlights the crucial role of the immune system in atherogenesis.