Mesothelin (Msln) expression is increased in tissue fibroblasts of damaged liver and other organs and Msln is a common mediator of liver, lung, and kidney fibrosis. We show that anti-Msln immunotoxins kill the Msln-expressing fibroblasts and reduce collagen type I deposition in fibrotic liver, indicating that agents that specifically kill Msln-expressing cells should be a useful treatment for cholestatic fibrosis. Targeting of Msln+ fibroblasts by anti-Msln immunoconjugates may become a strategy for the treatment of parenchymal organ fibrosis.
We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln−/− mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1−/− mice are more susceptible to fibrosis, suggesting that a Msln–Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)–injured mice.
We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.