Therapeutic advantage of anti-VAP-1 over anti-α4 integrin antibody in concanavalin a-induced hepatitis

Authors

  • Woo-Yong Lee,

    1. Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
    2. Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
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  • Marko Salmi,

    1. MediCity Research Laboratory, University of Turku, Turku, Finland
    2. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland
    3. National Institute of Health and Welfare, Turku, Finland
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  • Margaret M. Kelly,

    1. Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
    2. Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
    3. Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
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  • Sirpa Jalkanen,

    1. MediCity Research Laboratory, University of Turku, Turku, Finland
    2. National Institute of Health and Welfare, Turku, Finland
    3. Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland
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  • Paul Kubes

    Corresponding author
    1. Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
    • Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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  • Potential conflict of interest: Nothing to report.

  • Supported by the Canadian Association of Gastroenterology/Crohn's and Colitis Foundation of Canada Fellowship Award.

Address reprint requests to: Paul Kubes, Ph.D., Department of Physiology & Pharmacology, Faculty of Medicine, University of Calgary, HRIC 4AA16, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada. E-mail: pkubes@ucalgary.ca; fax: 403-270-7516.

Abstract

Hepatitis induced by concanavalin A (Con A) in mice is well known to be a T-lymphocyte-mediated injury. It has been reported that T helper (Th)1 and Th2 lymphocytes use α4 integrin and vascular adhesion protein (VAP)−1, respectively, to adhere within the hepatic sinusoids. Therefore, we investigated whether inhibition of these molecules ameliorates or worsens the Con A-induced hepatic injury in vivo. Vehicle or antibody to α4 integrin or VAP-1 was intravenously administered 30 minutes before Con A administration. In control mice Con A markedly increased the serum alanine aminotransferase (ALT) level in a dose-dependent manner, and induced a massive infiltration of CD3, particularly interleukin (IL)−4 producing CD4 T cells and liver injury. Both parameters were reduced by anti-VAP-1 antibody despite antibody only blocking the adhesion, not the amine oxidase activity of VAP-1. Both activities of VAP-1 were eliminated in VAP-1-deficient mice and both Con A-induced liver injury and CD4 T-cell infiltration were eradicated. In contrast to anti-VAP-1, anti-α4 integrin antibody reduced interferon-gamma (IFN-γ)-producing CD3 T cells but this worsened Con A hepatitis, suggesting inhibition of a suppressor cell. Con A induced the recruitment of CD49d+ monocytic myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) into the liver. Anti-α4 integrin dramatically blocked the influx of MDSCs but not Tregs. Conclusion: Our findings show that VAP-1 and α4 integrin have opposing effects in Con A-induced hepatic injury, which is associated with blocking the recruitment of CD4 lymphocytes and monocytic MDSCs, respectively. Moreover, these data provide the rationale for a potential therapeutic approach to target adhesion molecules in autoimmune hepatitis. (Hepatology 2013;58:1413–1423)

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