β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis

Authors

  • W. Zhang,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
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  • Y. Moritoki,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
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  • K. Tsuneyama,

    1. Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama, Japan,
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  • G.-X. Yang,

    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
    2. Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel, and
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  • Y. Ilan,

    1. Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel, and
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  • Z.-X. Lian,

    Corresponding author
    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
    2. Institute of Immunology and School of Life Sciences, University of Science and Technology of China, Hefei, China
    • M. E. Gershwin and Z.-X. Lian, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
      E-mail: megershwin@ucdavis.edu, zxlian@ucdavis.edu

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  • M. E. Gershwin

    Corresponding author
    1. Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
    • M. E. Gershwin and Z.-X. Lian, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
      E-mail: megershwin@ucdavis.edu, zxlian@ucdavis.edu

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Summary

We have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor-β receptor (dnTGF-βRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8+ T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8+ T cells, we have determined herein whether administration of β-glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8+ T cell responses and to down-regulate tissue inflammation. Accordingly, dnTGF-βRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liver-infiltrating CD8+ T cells, accompanied by a significant decrease in activated CD44high CD8+ T cell populations. Further, there was a significant reduction in portal inflammation in GC-treated mice. Interestingly, there were no changes in anti-mitochondrial antibodies, CD4+ T cells, CD19+ B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liver-infiltrating CD8+ T cells. These data suggest that further work on GC in models of CD8+ T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease.

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