title: Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-β1.
abstract: Transforming growth factor β1 (TGF-β1) is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-β1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-β1 with TGF-β1 kinoids. Two TGF-β1 kinoid vaccines were prepared by cross-linking TGF-β1-derived polypeptides (TGF-β1(25)-[41-65] and TGF-β1(30)-[83-112]) to keyhole limpet hemocyanin (KLH). Immunization with the two TGF-β1 kinoids efficiently elicited the production of high-levels of TGF-β1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The antisera neutralized TGF-β1-induced growth-inhibition on mink lung epithelial cells (Mv1Lu) and attenuated TGF-β1-induced Smad2/3 phosphorylation, α-SMA, collagen type 1 alpha 2 (COL1A2), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression in the rat hepatic stellate cell (HSC) line, HSC-T6. Vaccination against TGF-β1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of α-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-β1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-β1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases.
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Xiaobao
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Qiannan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Houqiang
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Huiping
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Gastroenterology, the First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Hao
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D017209:Apoptosis; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D055166:Hepatic Stellate Cells / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology*; D014611:Vaccination
chemical_list: D057134:Antibodies, Neutralizing; D007106:Immune Sera; D007074:Immunoglobulin G; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride