Development and Characterization of a Rodent Model of Immune-Mediated Cholangitis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 93; no. 1; pp. 216 - 220
• Main Authors: Ueno, Yoshiyuki, Phillips, John O., Ludwig, Jurgen, Lichtman, Steven N., LaRusso, Nicholas F.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 09-01-1996; National Acad Sciences; National Academy of Sciences
• Subjects: Animal models; Animals; Bile ducts; Bile Ducts - cytology; Bile Ducts - immunology; Cholangitis; Cholangitis - immunology; Cholangitis - pathology; Cytotoxicity; Cytotoxicity, Immunologic; Disease; Disease Models, Animal; Epithelium - immunology; Immunity (Disease); Immunity, Cellular; Immunization; Immunization, Passive; Inflammation; Liver; Male; Medical research; Rats; Rats, Inbred F344; Rats, Wistar; Rodents; Splenocytes; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.1.216

The cholangiopathies are a group of hepatobiliary diseases in which intrahepatic bile duct epithelial cells, or cholangiocytes, are the target for a variety of destructive processes, including immune-mediated damage. We tested the hypothesis that cholangitis could be induced in rodents by immunization with highly purified cholangiocytes. Inbred Wistar rats were immunized with purified hyperplastic cholangiocytes isolated after bile duct ligation from either syngeneic Wistar or allogeneic Fischer 344 rats; control rats were immunized with bovine serum albumin (BSA) or hepatocytes. After immunization with cholangiocytes, recipient animals developed histologic evidence of nonsuppurative cholangitis without inflammation in other organs; groups immunized with BSA or hepatocytes showed no cholangitis. Immunohistochemical studies revealed that portal tract infiltrates around bile ducts consisted of CD3-positive lymphocytes, some of which expressed major histocompatibility complex class II antigen; B cells and exogenous monocytes/macrophages were essentially absent. Transfer of unfractionated Con-A-stimulated spleen cells from cholangiocyte-immunized (but not BSA-immunized) rats into recipients also caused nonsuppurative cholangitis. Moreover, these splenocytes from cholangiocyte-immunized (but not BSA-immunized) rats were cytotoxic in vitro for cultured rodent cholangiocytes; no cytotoxicity was observed against a rat hepatocyte cell line. Also, a specific antibody response in sera of cholangiocyte-immunized rats was demonstrated by immunoblots against cholangiocyte proteins. Finally, cholangiograms in cholangiocyte-immunized rats showed distortion and tortuosity of the entire intrahepatic biliary ductal system. This unique rodent model of experimental cholangitis demonstrates the importance of immune mechanisms in the pathogenesis of cholangitis and will prove useful in exploring the mechanisms by which the immune system targets and damages cholangiocytes.