TGFβ2 and TGFβ3 isoforms drive fibrotic disease pathogenesis
Tianhe Sun, Zhiyu Huang, Wei‐Ching Liang, Jianping Yin, WeiYu Lin, Jia Wu, Jean-Michel Vernes, Jeff Lutman, Patrick Caplazi, Surinder Jeet, Tiffany Wong, Manda Wong, Daryle J. DePianto, Katrina B. Morshead, Kai-Hui Sun, Zora Modrušan, Jason A. Vander Heiden, Alexander R. Abbas, Hua Zhang, Min Xu, Elsa-Noah N’Diaye, Meron Roose-Girma, Paul J. Wolters, Rajbharan Yadav, Siddharth Sukumaran, Nico Ghilardi, Racquel Corpuz, Claire Emson, Yumin Meng, Thirumalai R. Ramalingam, Patrick J. Lupardus, Hans D. Brightbill, Dhaya Seshasayee, Yan Wu, Joseph R. Arron
Abstract
expression is increased in human lung and liver fibrotic tissues compared to healthy control tissues. Thus, TGFβ2 and TGFβ3 may play a pathological role in fibrosis. Inducible conditional knockout mice and anti-TGFβ isoform-selective antibodies demonstrated that TGFβ2 and TGFβ3 are independently involved in mouse fibrosis models in vivo, and selective TGFβ2 and TGFβ3 inhibition does not lead to the increased inflammation observed with pan-TGFβ isoform inhibition. A cocrystal structure of a TGFβ2-anti-TGFβ2/3 antibody complex reveals an allosteric isoform-selective inhibitory mechanism. Therefore, inhibiting TGFβ2 and/or TGFβ3 while sparing TGFβ1 may alleviate fibrosis without toxicity concerns associated with pan-TGFβ blockade.