Therapeutic effect of CTLA4-Ig on a murine model of primary biliary cirrhosis

• Type of Material: Article
• Authors: Amy Dhirapong, University of California; Guo-Xiang Yang, University of California; Steven Nadler, Bristol Myers Squibb; Weici Zhang, University of California; Koichi Tsuneyama, University of California; Patrick Leung, University of California; Stuart J Knechtle, Emory University; Aftab A Ansari, Emory University; Ross L. Coppel, Monash University; Fu-Tong Liu, University of California; Xiao-Song He, University of California; M. Eric Gershwin, University of California
• Language: English
• Date: 2013-02
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Association for the Study of Liver Diseases
• Final Published Version (URL): http://onlinelibrary.wiley.com/doi/10.1002/hep.26067/abstract?systemMessage=Wiley+Online+Library+will+be+disrupted+Saturday%2C+15+March+from+10%3A00-12%3A00+GMT+%2806%3A00-08%3A00+EDT%29+for+essential+maintenance
• Title of Journal or Parent Work: Hepatology
• ISSN: 0270-9139
• Volume: 57
• Issue: 2
• Start Page: 708
• End Page: 715
• Grant/Funding Information: Financial support provided by a grant from the National Institutes of Health, DK067003.
• Keywords: cholangitis; Abatacept autoimmunity; Primary biliary cirrhosis; cytotoxic T lymphocyte antigen 4
• Research Categories: Health Sciences, Immunology

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 MHC and a set of co-stimulatory molecules which include a receptor on T cells coined cytotoxic T lymphocyte antigen 4 (CTLA-4). Germane to the studies reported herein, signaling via CTLA-4 has the potential to modulate co-stimulation 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 BSA, leading to the production of high titer anti-mitochondrial autoantibodies and portal cellular infiltrates. To investigate the potential of CTLA-4 Ig as an immunotherapeutic agent, we treated mice both before and after induction of autoimmune cholangitis. Firstly, we demonstrate that CTLA-4 Ig treatment begun one day before 2-OA-BSA immunization, completely inhibits the manifestations of cholangitis, including AMA production, intra-hepatic 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 intra-hepatic T cell infiltrates and biliary cell damage, although AMA levels were not altered. 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.