title: Deletion of Smad3 improves cardiac allograft rejection in mice.
abstract: T cells play a critical role in acute allograft rejection. TGF-β/Smad3 signaling is a key pathway in regulating T cell development. We report here that Smad3 is a key transcriptional factor of TGF-β signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1β, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+ T cells, and F4/80+ macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-γ while enhancing GATA3 and IL-4 expression, resulting in a shift from the Th1 to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed. In conclusion, Smad3 is an immune regulator in T cell-mediated cardiac allograft rejection. Loss of Smad3 results in a shift from Th1 to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-β/Smad3 signaling may be a novel therapy for acute allograft rejection.
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Wang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.|Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.|Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Pan
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhang-Fei
authors.initials: ZF
authors.lastname: Shou
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Xiang
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Da-Jin
authors.initials: DJ
authors.lastname: Chen
authors.affiliation: Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.|Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Hui-Yao
authors.initials: HY
authors.lastname: Lan
authors.affiliation: Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jiang-Hua
authors.initials: JH
authors.lastname: Chen
mesh_terms: D064591:Allografts; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D051900:Smad3 Protein / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014181:Transplantation Immunology / Q000276:immunology*
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse
keywords: Pathology Section; Smad3; Th1; Th17; Th2; cardiac allograft rejection