Effect of an immunotoxin to folate receptor β on bleomycin-induced experimental pulmonary fibrosis

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SummaryIt has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed folate receptor β (FRβ) while resident macrophages in normal tissues expressed no or low levels of FRβ. In the present study, we examined the distribution of FRβ-expressing macrophages in the lungs of patients with usual idiopathic pulmonary fibrosis (UIP) and mice with bleomycin-induced pulmonary fibrosis (PF) and tested whether the depletion of FRβ-expressing macrophages could suppress bleomycin-induced PF in mice. Immunostaining with anti-human or -mouse FRβ monoclonal antibody (mAb) revealed that FRβ-expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with UIP and mice with bleomycin-induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FRβ mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin-induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor-α-, chemokines CCL2- and CCL12-producing cells were observed in the immunotoxin-treated group. These findings suggest a pathogenic role of FRβ-expressing macrophages in IPF. Thus, targeting FRβ-expressing macrophages may be a promising treatment of IPF.

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