@article{12a52356383b4582b9f4b464bd707754,
title = "Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis",
abstract = "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.",
keywords = "Activated portal fibroblasts, Cholestatic fibrosis, Mesothelin",
author = "Takahiro Nishio and Yukinori Koyama and Xiao Liu and Rosenthal, {Sara B.} and Gen Yamamoto and Hiroaki Fuji and Jacopo Baglieri and Na Li and Brenner, {Laura N.} and Keiko Iwaisako and Kojiro Taura and Hagood, {James S.} and LaRusso, {Nicholas F.} and Bera, {Tapan K.} and Ira Pastan and Brenner, {David A.} and Tatiana Kisseleva",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Ms. Karin Diggle for excellent technical assistance and Drs. Simon S. Wong, Thomas Whisenant, Katrin Hochrath, and Mojgan Hosseini (University of California San Diego) for help with experiments. This work was supported by NIH R01DK101737, U01AA022614, and R01DK099205, R01DK111866 (to T.K.), R01DK101737 (to D.A.B.), R01DK09920 (to D.A.B.), P50AA011999 (to T.K. and D.A.B.), and AI043477 (to D.A.B.). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = jul,
day = "20",
doi = "10.1073/pnas.2101270118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "29",
}