Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance

Authors

  • Pascal Lapierre,

    Corresponding author
    1. Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Quebec, Canada
    • Ph.D., Laboratory of Immunovirology, INRS-Institut Armand-Frappier, 531, boul. des Prairies, Laval, Quebec, H7V 1B7, Canada
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  • Kathie Béland,

    1. Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Quebec, Canada
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  • Roland Yang,

    1. Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Quebec, Canada
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  • Fernando Alvarez

    1. Division of Gastroenterology, Hepatology and Nutrition, Sainte-Justine University Hospital, Montreal, Quebec, Canada
    2. Department of Microbiology and Immunology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
    3. Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
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  • Potential conflict of interest: Nothing to report.

Abstract

Autoimmune hepatitis (AIH) is characterized by a loss of immunological tolerance to hepatocytes. Patients respond well to immunosuppression but progression to endstage liver disease occurs in 10%-20% of cases, leading to liver transplantation. Using a murine model of type 2 AIH, we identified susceptibility factors for autoimmune hepatitis and attempted to restore immunological tolerance to liver autoantigens. An increased ectopic expression of a liver autoantigen (FTCD) in the thymus leading to reduced numbers of circulating autoreactive T cells was sufficient to prevent development of AIH in mice. However, in the presence of a reduced central tolerance to FTCD, a strong regulatory T-cell response was able to inhibit proliferation of liver-specific autoreactive T cells and prevent AIH. Development of a severe AIH stemmed from reduced numbers of functional regulatory T cell (Tregs) leading to an increased proliferation of FTCD-specific autoreactive T and B cells. Adoptive transfer of ex vivo expanded CXCR3+ Tregs in mice with AIH efficiently targeted the inflamed liver, restored peripheral tolerance to FTCD, and induced remission of AIH. Conclusion: Peripheral tolerance to liver autoantigens in AIH is paramount. Autologous infusion of ex vivo expanded CXCR3+ Tregs in AIH patients could be an effective therapeutic approach to restore peripheral tolerance and induce remission of AIH. (HEPATOLOGY 2013)

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