Development and characterization of a rodent model of immune-mediated cholangitis

Yoshiyuki Ueno, John O. Phillips, Jurgen Ludwig, Steven N. Lichtman, Nicholas F La Russo

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)216-220
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number1
DOIs
StatePublished - Jan 9 1996

Fingerprint

Cholangitis
Rodentia
Bovine Serum Albumin
Hepatocytes
Bile Ducts
Immunization
Intrahepatic Bile Ducts
Histocompatibility Antigens Class II
Inbred F344 Rats
Biliary Tract
Major Histocompatibility Complex
Antibody Formation
Ligation
Wistar Rats
Monocytes
Immune System
B-Lymphocytes
Theoretical Models
Spleen
Epithelial Cells

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Development and characterization of a rodent model of immune-mediated cholangitis. / Ueno, Yoshiyuki; Phillips, John O.; Ludwig, Jurgen; Lichtman, Steven N.; La Russo, Nicholas F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 1, 09.01.1996, p. 216-220.

Research output: Contribution to journalArticle

@article{4683099239de49609ee66d7fb1dd5968,
title = "Development and characterization of a rodent model of immune-mediated cholangitis",
abstract = "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.",
author = "Yoshiyuki Ueno and Phillips, {John O.} and Jurgen Ludwig and Lichtman, {Steven N.} and {La Russo}, {Nicholas F}",
year = "1996",
month = "1",
day = "9",
doi = "10.1073/pnas.93.1.216",
language = "English (US)",
volume = "93",
pages = "216--220",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "1",

}

TY - JOUR

T1 - Development and characterization of a rodent model of immune-mediated cholangitis

AU - Ueno, Yoshiyuki

AU - Phillips, John O.

AU - Ludwig, Jurgen

AU - Lichtman, Steven N.

AU - La Russo, Nicholas F

PY - 1996/1/9

Y1 - 1996/1/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0030025595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030025595&partnerID=8YFLogxK

U2 - 10.1073/pnas.93.1.216

DO - 10.1073/pnas.93.1.216

M3 - Article

C2 - 8552608

AN - SCOPUS:0030025595

VL - 93

SP - 216

EP - 220

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 1

ER -