CD3 Antibody and IL‐2 Complex Combination Therapy Inhibits Atherosclerosis by Augmenting a Regulatory Immune Response

BACKGROUND: Accumulating evidence suggests that the balance between pathogenic effector T cells (Teffs) and regulatory T cells (Tregs) may be important for controlling atherosclerotic disease. We hypothesized that a combination therapy with anti‐CD3 antibody (CD3‐Ab) and IL‐2/anti‐IL‐2 monoclonal antibody complex (IL‐2 complex) aimed at increasing the ratio of Tregs to Teffs would effectively inhibit atherosclerosis in mice. METHODS AND RESULTS: We treated apolipoprotein E‐deficient mice fed a high‐cholesterol diet with vehicle, CD3‐Ab, IL‐2 complex, or their combination. Mice receiving the combination therapy had markedly reduced atherosclerotic lesions than mice treated with CD3‐Ab or IL‐2 complex alone. In addition, a striking increase in the Treg/Teff ratio of lymphoid organs and atherosclerotic lesions, along with plaque stabilization characterized by decreased macrophage content and increased collagen content was observed. The combination treatment also markedly reduced splenic Ly6C(high) inflammatory monocytes and might induce a favorable macrophage phenotype change in atherosclerotic lesions. CONCLUSIONS: Our results indicate that in addition to suppressing Teff responses, enhancing Treg‐mediated immune responses is more efficacious in preventing atherosclerosis, suggesting a novel therapeutic approach for atherosclerosis.