Abstract
BackgroundFolate receptor β (FRβ) is induced during macrophage activation. A recombinant immunotoxin consisting of the truncated Pseudomonas exotoxin A (PE38) conjugated to an anti-FRβ antibody (anti–FRβ-PE38) has been reported to kill activated macrophages in inflammatory diseases. To elucidate the effect of an immunotoxin targeting FRβ on atherosclerosis, we determined the presence of FRβ-expressing macrophages in atherosclerotic lesions and administered the FRβ immunotoxin in apolipoprotein E–deficient mice.Methods and ResultsThe FRβ-expressing macrophages were observed in atherosclerotic lesions of apolipoprotein E–deficient mice. At 15 or 35 weeks of age, the apolipoprotein E–deficient mice were divided into 3 groups and were intravenously administered 0.1 mg/kg of anti–FRβ-PE38 (immunotoxin group), 0.1 mg/kg of PE38 (toxin group), or 0.1 mL of saline (control group) every 3 days, for a total of 5 times for each age group. The mice were analyzed at 21 or 41 weeks of age. Treatment with the immunotoxin resulted in 31% and 22% reductions in atherosclerotic lesions of the 21- and 41-week-old mice, respectively (P<0.05). Administration of immunotoxin reduced the numbers of FRβ- and tumor necrosis factor-α–expressing macrophages, reduced cell proliferation, and increased the number of apoptotic cells (P<0.05). Real-time polymerase chain reaction demonstrated that the expression of FRβ and tumor necrosis factor-α mRNA was significantly decreased in the immunotoxin group (P<0.05).ConclusionsThese results suggest that FRβ-expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E–deficient mice and that FRβ immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals. The recombinant FRβ immunotoxin targeting activated macrophages could provide a novel therapeutic tool for atherosclerosis. (J Am Heart Assoc. 2012;1:e003079 doi: 10.1161/JAHA.112.003079.)
Highlights
ObjectivesThe purpose of the present study was to determine the presence of FRb-expressing macrophages in atherosclerotic lesions and to investigate the effect of the recombinant anti– FRb-PE38 immunotoxin administered at an early or late stage of atherosclerosis in a murine model of experimental atherosclerosis
Conclusions-—These results suggest that FRb-expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E–deficient mice and that FRb immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals
It has been reported previously that FRb is expressed on activated macrophages at the site of inflammation.[11]
Summary
The purpose of the present study was to determine the presence of FRb-expressing macrophages in atherosclerotic lesions and to investigate the effect of the recombinant anti– FRb-PE38 immunotoxin administered at an early or late stage of atherosclerosis in a murine model of experimental atherosclerosis
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