Research Papers: Pathology:
Deletion of Smad3 improves cardiac allograft rejection in mice
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Ying-ying Wang1,2,*, Hong Jiang1,*, Yu-cheng Wang1,2, Xiao-ru Huang2,3, Jun Pan2,4, Chen Yang2, Zhang-fei Shou1, Shi-long Xiang1, Da-jin Chen1, Hui-yao Lan2,3 and Jiang-hua Chen1
1 Kidney Disease Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
2 Li Ka Shing Institute of Health Sciences, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
3 Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
4 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
* These authors contributed to this work equally
Jiang-hua CHEN, email:
Hui-Yao LAN, email:
Keywords: Smad3, cardiac allograft rejection, Th1, Th2, Th17, Pathology
Received: May 05, 2015 Accepted: June 23, 2015 Published: July 13, 2015
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.
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