Get access

Low-dose anti-CD3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice

Authors

  • Gabriel Marceau,

    1. Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
    Search for more papers by this author
    • These authors contributed equally to this work
  • Roland Yang,

    1. Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
    2. Department of Microbiology & Immunology, University of Montréal, Montréal, QC, Canada
    Search for more papers by this author
    • These authors contributed equally to this work
  • Pascal Lapierre,

    1. INRS – Institut Armand-Frappier, Laval, QC, Canada
    Search for more papers by this author
  • Kathie Béland,

    1. Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
    Search for more papers by this author
  • Fernando Alvarez

    Corresponding author
    1. Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, Montréal, QC, Canada
    2. Department of Microbiology & Immunology, University of Montréal, Montréal, QC, Canada
    3. Department of Pediatrics, Faculty of Medicine, University of Montréal, Montréal, QC, Canada
    • Correspondence

      Fernando Alvarez, MD, 3175, Chemin de la Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada

      Tel: 1-514-345-4626

      Fax: 1-514-345-4999

      e-mail: fernando.alvarez@umontreal.ca

    Search for more papers by this author

Abstract

Background

Some patients with autoimmune hepatitis (AIH), despite appropriate treatment, progress towards cirrhosis and liver failure, requiring transplantation. New biological agents targeting immune cell subtypes have been developed, with better specificity and longer-lasting effects than conventional wide-spectrum immunosuppressive drugs.

Aims

The goal of this study was to evaluate the effectiveness of low dose of αCD3 targeting therapy in a model of type 2 AIH.

Methods

This experimental model is based on xenoimmunization of C57BL/6 mice with DNA coding for human liver autoantigens. Mice with AIH were treated with five daily injections of low dose of αCD3 monoclonal antibody, before disease onset (5.5 months post-xenoimmunization) or during AIH (7 months post-xenoimmunization). Along with serum aminotransferases, autoantibody levels and end-point liver histology, spleen and liver-infiltrating lymphocytes were phenotyped by flow cytometry and immune response measured by lymphoproliferative assays.

Results

Before onset of AIH, treatment prevented the development of liver inflammation and tissue injury. During active AIH, low dose of αCD3 antibody therapy resulted in a resorption of liver inflammatory infiltrates, normalization of serum aminotransferas levels, reduced autoantibody titres, increased regulatory T cells and lowered proliferation of autoreactive liver lymphocytes.

Conclusions

We report that low dose αCD3 antibody administration is an effective treatment for AIH in an experimental model of type 2 AIH. These data suggest that αCD3 antibody therapy could be tested in clinical trials as a rescue therapy for patients with uncontrolled AIH.

Ancillary