title: Low-dose anti-CD3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice.
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.
  
  
  OBJECTIVE
  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.
authors: Division of Gastroenterology, Hepatology & Nutrition, CHU Sainte-Justine, Montréal, QC, Canada.
authors: Gabriel
authors: G
authors: Marceau
authors: Roland
authors: R
authors: Yang
authors: Pascal
authors: P
authors: Lapierre
authors: Kathie
authors: K
authors: Béland
authors: Fernando
authors: F
authors: Alvarez
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001324:Autoantigens / Q000008:administration & dosage; D017252:CD3 Complex / Q000276:immunology*; D005434:Flow Cytometry; D019693:Hepatitis, Autoimmune / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D012074:Remission Induction / Q000379:methods; D000637:Transaminases / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D017252:CD3 Complex; D000637:Transaminases
keywords: T Cells; autoimmune hepatitis; immunotherapy; liver; regulatory T cells