Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis12. Issue 2 (5th February 2013)

• Record Type: Journal Article
• Authors: Dhirapong, Amy; Yang, Guo‐Xiang; Nadler, Steven; Zhang, Weici; Tsuneyama, Koichi; Leung, Patrick; Knechtle, Stuart; Ansari, Aftab A.; Coppel, Ross L.; Liu, Fu‐Tong; He, Xiao‐Song; Gershwin, M. Eric
• Is Part Of: Hepatology. Volume 57:Issue 2(2013:Feb.)
• Page Start: 708
• Page End: 715
• Publication Date: 2013-02-05
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26067
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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. <italic>Conclusion</italic>: 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. (H<sc>EPATOLOGY</sc> 2013)</p> </abstract>