Abstract 12787: Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor β-Expressing Macrophages
Introduction: Folate receptor (FR) with a high affinity for folic acid has three isoforms (α, β, γ) and folate receptor β (FRβ) is induced during macrophage activation. A recombinant immunotoxin consisted of the truncated Pseudomonas exotoxin A (PE38) conjugated to a disulfide-stabilized fragment of variable region of anti-FRβ antibody (dsFv anti-FRβ-PE38) has been reported to kill activated macrophages in inflammatory diseases such as rheumatoid arthritis and pulmonary fibrosis. However, the effect of an immunotoxin targeting FRβ on atherosclerosis has not been elucidated.
Hypothesis: Macrophages in atherosclerotic lesion express FRβ and the recombinant immunotoxin targeting FRβ (dsFv anti-FRβ-PE38) decreases the atherosclerosis in apolipoprotein E (apoE)-deficient mice.
Methods: We performed immunohistochemistry to analyze the localization of CD68 or FRβ-expressing macrophages in the atherosclerotic lesion of apoE-deficient mice at 35 weeks of age. Furthermore, we analyzed the effect of recombinant immunotoxin on atherosclerosis. At 15 weeks of age, apoE-deficient mice were divided into 3 groups and administered 0.1mg/kg of dsFv anti-FRβ-PE38 (immunotoxin group, n=8), 0.1mg/kg of PE38 (toxin group, n=8), or 0.1ml of saline (control group, n=8) intravenously every 3 days, totally 5 times. At 21 weeks of age, atherosclerotic lesions in the aortic root were measured by a quantitative assay.
Results: Immunohistochemistry demonstrated that CD68-expressing macrophages were stained in the whole area of intima and FRβ-expressing macrophages were mainly detected in the intimal elastic lamina side of intima. Treatment with the immunotoxin using the dsFv anti-FRβ-PE38 resulted in 31% reduction of atherosclerotic lesions compared to the control and toxin groups (P<0.05). The number of peripheral blood monocytes, the serum levels of total cholesterol, and body weight were not different among these 3 groups.
Conclusions: This is the first report to demonstrate the presence of FRβ-expressing macrophages in the atherosclerotic lesion. The recombinant immunotoxin targeting activated macrophages reduced the atherosclerotic lesion, and will provide a novel therapeutic tool for atherosclerosis.
- © 2010 by American Heart Association, Inc.