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TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Cellular & Molecular Immunology volume 10, pages 165–175 (2013)Cite this article

Abstract

Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4−/−) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4−/− mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4+/+) mice. In addition, histopathological analyses revealed that in TLR4−/−→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4+/+, TLR4−/− mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4−/− mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4+/+ mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4−/−→BALB/c than in TLR4+/+→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.

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Acknowledgements

We are grateful to Miao Chen, Qiangguo Gao and Yiqi Liu (Second Military Medical University, Shanghai, China) for technical support and offer special thanks to Professor Qing Yi (M.D. Anderson Cancer Center; Houston, TX, USA) for helpful guidance in the experiments. We thank Shizuo Akira (Osaka University, Osaka, Japan) for originally providing key mouse strains. This work was supported by grants of the National Natural Science Foundation of China (no. 30772502 and 30973455), Zhejiang Major Medical and the Health Science and Technology & Ministry of Health of the Chinese Government (no. WKJ2009-2-022). This work was also supported by the Major Research Plan of the Chinese National Natural Science Foundation (no. 91029740), Zhejiang Province Science and Technology Department Foundation (no. 2009C03012-2) and Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents.

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  1. Yi Zhao, Qiuyan Liu and Li Yang: These authors contributed equally to this work.

  2. Dr Z Cai, Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. E-mail: caizhen1@yahoo.com

Authors and Affiliations

  1. Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yi Zhao, Li Yang, Donghua He, Lijuan Wang, Yi Li, Fuming Zi, Hanying Bao, Yang Yang, Jimin Shi, Xingkui Xue & Zhen Cai

  2. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, China

    Qiuyan Liu, Jun Tian & Yuanyuan Zheng

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Zhao, Y., Liu, Q., Yang, L. et al. TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 10, 165–175 (2013). https://doi.org/10.1038/cmi.2012.58

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