Brigle KE

Nagai T

Ogata M

Pastan I

Rekhter MD

Shah SA

Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease


            Background
            
              Folate receptor β (
              FR
              β) is induced during macrophage activation. A recombinant immunotoxin consisting of the truncated
              
                P
                seudomonas
              
              exotoxin A (
              PE
              38) conjugated to an anti‐
              FR
              β antibody (anti–
              FR
              β‐
              PE
              38) has been reported to kill activated macrophages in inflammatory diseases. To elucidate the effect of an immunotoxin targeting
              FR
              β on atherosclerosis, we determined the presence of
              FR
              β‐expressing macrophages in atherosclerotic lesions and administered the
              FR
              β immunotoxin in apolipoprotein E–deficient mice.
            
          
          
            Methods and Results
            
              The
              FR
              β‐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
              &lt;0.05). Administration of immunotoxin reduced the numbers of
              FR
              β‐ and tumor necrosis factor‐α–expressing macrophages, reduced cell proliferation, and increased the number of apoptotic cells (
              P
              &lt;0.05). Real‐time polymerase chain reaction demonstrated that the expression of
              FR
              β and tumor necrosis factor‐α
              mRNA
              was significantly decreased in the immunotoxin group (
              P
              &lt;0.05).
            
          
          
            Conclusions
            
              These results suggest that
              FR
              β‐expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E–deficient mice and that
              FR
              β immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals. The recombinant
              FR
              β immunotoxin targeting activated macrophages could provide a novel therapeutic tool for atherosclerosis.
            
          </jats:sec

Yuko Furusho

Masaaki Miyata

Takami Matsuyama

Taku Nagai

Hua Li

Yuichi Akasaki

Narisato Hamada

Takahiro Miyauchi

Yoshiyuki Ikeda

Takahiro Shirasawa

Kanako Ide

Chuwa Tei

Crossref

Journal of the American Heart Association

Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor β–Expressing Macrophages

Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor β–Expressing Macrophages

Abstract

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