Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis

Amy Dhirapong, Guo Xiang Yang, Steven Nadler, Weici Zhang, Koichi Tsuneyama, Patrick S Leung, Stuart Knechtle, Aftab A. Ansari, Ross L. Coppel, Fu-Tong Liu, Xiaosong He, M. Eric Gershwin

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78 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)708-715
Number of pages8
JournalHepatology
Volume57
Issue number2
DOIs
StatePublished - Feb 2013

ASJC Scopus subject areas

  • Hepatology

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    Dhirapong, A., Yang, G. X., Nadler, S., Zhang, W., Tsuneyama, K., Leung, P. S., Knechtle, S., Ansari, A. A., Coppel, R. L., Liu, F-T., He, X., & Gershwin, M. E. (2013). Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology, 57(2), 708-715. https://doi.org/10.1002/hep.26067