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Natural killer T cells mediate inflammation in the bile ducts

Mucosal Immunologyvolume 11pages15821590 (2018) | Download Citation

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Abstract

Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d−/− mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days. NKT cells were activated after intrabiliary injection of oxazolone with upregulation of activation markers. Cd1d−/− and wild-type mice pretreated with antibody blocking of CD1d were protected from disease. These findings implicate that cells in the bile ducts function as antigen-presenting cells in vivo and activate NKT cells in a CD1d-restricted manner. The elucidation of this biliary immune pathway opens up for potentially new therapeutic approaches for cholangiopathies.

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Acknowledgements

The authors wish to thank Anne Pharo, Lisa Yuen Løvold, Liv Wenche Thorbjørnsen, Tonje Bjørnetrø, Hege Dahlen Sollid and Eva Kristine Klemsdal Henriksen at the Norwegian PSC Research Center, as well as Ellen Hellesylt at Laboratory of Immunohistochemistry, Department of Pathology, Radiumhospitalet, for great assistance and technical help. Loaded and unloaded PBS-57 CD1d tetramers were kindly provided by the NIH Tetramer Core, Emory, GA, USA. The study was supported by South Eastern Norway Regional Health Authority (project number 2013020), PSC Partners Seeking a Cure and the Norwegian PSC Research Center. R.S.B. was supported by NIH DK44319.

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Affiliations

  1. Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway

    • N. L. Berntsen
    • , B. Fosby
    • , C. Tan
    • , X. Jiang
    • , E. Schrumpf
    • , L. Valestrand
    • , T. H. Karlsen
    •  & E. Melum
  2. Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway

    • N. L. Berntsen
    • , J. Ogaard
    • , X. Jiang
    • , E. Schrumpf
    • , L. Valestrand
    • , T. H. Karlsen
    •  & E. Melum
  3. Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway

    • B. Fosby
    •  & P.-D. Line
  4. Department of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway

    • H. M. Reims
  5. Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway

    • T. H. Karlsen
    •  & E. Melum
  6. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    • T. H. Karlsen
    • , P.-D. Line
    •  & E. Melum
  7. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    • R. S. Blumberg

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Contributions

N.L.B.: study concept and design, acquisition of data, statistical analysis and interpretation of data and drafting of the manuscript. C.T., L.V. and J.O.: acquisition of data, technical support and critical revision of the manuscript for important intellectual content. B.F., X.J. and E.S.: study concept and design and critical revision of the manuscript for important intellectual content. H.M.R., T.H.K. and P.-D.L.: study concept and design and critical revision of the manuscript for important intellectual content. R.S.B.: study concept and design, interpretation of data and critical revision of the manuscript for important intellectual content. E.M.: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, obtained funding and study supervision.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to E. Melum.

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DOI

https://doi.org/10.1038/s41385-018-0066-8