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Kupffer cell-derived IL-10 plays a key role in maintaining humoral immune tolerance in hepatitis B virus-persistent mice

Authors

  • Long Xu,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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    • These authors contributed equally to this work.

  • Wenwei Yin,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
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    • These authors contributed equally to this work.

  • Rui Sun,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
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  • Haiming Wei,

    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
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  • Zhigang Tian

    Corresponding author
    1. Department of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China
    2. Hefei National Laboratory for Physical Sciences at Microscale, Hefei, Anhui, China
    • Address reprint requests to: Zhigang Tian, M.D., Ph.D., School of Life Sciences, University of Science and Technology of China 443 Huangshan Road, Hefei, Anhui 230027, China. E-mail: tzg@ustc.edu.cn; fax: +86-551-6360-6783.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by the Natural Science Foundation of China (#91029303 and #31021061), the Ministry of Science and Technology of China (973 Basic Science Project: 2013CB944902 and 2012CB519004), and the National Science and Technology Major Projects (2012ZX10002006 and 2013ZX10002002-002). The authors thank Pei-Jer Chen (National Taiwan University) for the HBV plasmid pAAV/HBV1.2 and N.V. Rooijen (Vrije Universiteit) for the clodronate liposomes.

  • This work was supported by the Natural Science Foundation of China (#91029303 and #31021061), the Ministry of Science and Technology of China (973 Basic Science Project: 2013CB944902 and 2012CB519004), and the National Science and Technology Major Projects (2012ZX10002006 and 2013ZX10002002-002). The authors thank Pei-Jer Chen (National Taiwan University) for the HBV plasmid pAAV/HBV1.2 and N.V. Rooijen (Vrije Universiteit) for the clodronate liposomes.

Abstract

The liver is considered as a unique lymphoid organ favoring the induction of immune tolerance, rather than immunity. Biologists and clinicians alike have a long-standing interest in how the liver induces systemic immune tolerance, but the mechanism has not yet been well elucidated. Here, we employed hepatitis B virus (HBV)-carrier mice generated by hydrodynamically injecting phosphor-adeno-associated virus/HBV1.2 plasmid as a model for adult chronic HBV infection, which we found were unable to respond to hepatitis B surface antigen vaccination. Humoral tolerance induced in HBV-carrier mice could be transferred into Rag1−/− mice, because anti-HBV immunity in immunologically reconstituted Rag1−/− mice was inhibited by adoptive transfer of splenocytes from HBV-carrier mice. Humoral tolerance needed at least 7 days for induction and persisted to 3 months after a single HBV plasmid injection. Kupffer cell (KC) depletion or interleukin (IL-10) deficiency broke this humoral tolerance, and exogenous injection of IL-10 could effectively induce this tolerance. Conclusion: KCs in HBV-carrier mice expressed more IL-10 and mediated the systemic tolerance induction in an IL-10-dependent manner. This previously undescribed humoral tolerance regarding HBV infection will help to explore new approaches to reverse liver-sustained systemic immune tolerance in liver disease. (Hepatology 2014;59:443-452)

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