These authors contributed equally to this work.
Autoimmune, Cholestatic and Biliary Disease
Article first published online: 5 FEB 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 57, Issue 2, pages 708–715, February 2013
How to Cite
Dhirapong, A., Yang, G.-X., Nadler, S., Zhang, W., Tsuneyama, K., Leung, P., Knechtle, S., Ansari, A. A., Coppel, R. L., Liu, F.-T., He, X.-S. and Gershwin, M. E. (2013), Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology, 57: 708–715. doi: 10.1002/hep.26067
Potential conflict of interest: Dr. Nadler owns stock in Bristol-Myers Squibb.
Financial was support provided by a grant from the National Institutes of Health (DK067003).
- Issue published online: 5 FEB 2013
- Article first published online: 5 FEB 2013
- Accepted manuscript online: 19 SEP 2012 11:31AM EST
- Manuscript Accepted: 17 AUG 2012
- Manuscript Received: 17 JUL 2012
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. Conclusion: 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. (HEPATOLOGY 2013)