title: Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis.
abstract: Collectively, the data in both humans and murine models of human primary biliary cirrhosis (PBC) suggest that activated T cells, particularly CD8 T cells, play a critical role in biliary cell destruction. Under physiological conditions, T-cell activation involves two critical signals that involve the major histocompatibility complex and a set of costimulatory molecules, which include a receptor on T cells termed cytotoxic T lymphocyte antigen 4 (CTLA-4). Germane to the studies reported herein, signaling by CTLA-4 has the potential to modulate costimulation and induce inhibitory signals. In this study, we have taken advantage of our well-defined murine model of PBC, in which mice are immunized with 2-octynoic acid coupled to bovine serum albumin (2OA-BSA), leading to the production of high-titer antimitochondrial autoantibodies (AMAs) and portal cellular infiltrates. To investigate the potential of CTLA-4-Ig (immunoglobulin) as an immunotherapeutic agent, we treated mice both before and after induction of autoimmune cholangitis. First, we demonstrate that CTLA-4-Ig treatment, begun 1 day before 2OA-BSA immunization, completely inhibits the manifestations of cholangitis, including AMA production, intrahepatic T-cell infiltrates, and bile duct damage. However, and more critically, treatment with CTLA-4-Ig, initiated after the development of autoimmune cholangitis in previously immunized mice, also resulted in significant therapeutic benefit, including reduced intrahepatic T-cell infiltrates and biliary cell damage, although AMA levels were not altered.
  
  
  CONCLUSIONS
  These data suggest that an optimized regimen with CTLA-4-Ig has the potential to serve as an investigative therapeutic tool in patients with PBC.
authors.affiliation: Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Dhirapong
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Steven
authors.initials: S
authors.lastname: Nadler
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Patrick
authors.initials: P
authors.lastname: Leung
authors.forename: Stuart
authors.initials: S
authors.lastname: Knechtle
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000069594:Abatacept; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002761:Cholangitis / Q000188:drug therapy / Q000276:immunology; D004195:Disease Models, Animal; D005229:Fatty Acids, Monounsaturated; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008928:Mitochondria / Q000276:immunology
chemical_list: D005229:Fatty Acids, Monounsaturated; D018796:Immunoconjugates; C060855:2-octynoic acid; D000069594:Abatacept