Since the aetiopathogenesis of primary sclerosing cholangitis (PSC) in huma
ns remains undefined, investigators have studied a variety of animal models
to gain insights into immunopathogenetic mechanisms associated with oblite
rative fibrous cholangitis of intra- and extrahepatic bile ducts. To date,
no animal model has been developed that exhibits all of the attributes of P
SC. Rodent models instigated by bacteria] cell components or colitis are pr
omising because they may help to explain the strong association between PSC
and inflammatory bowel disease (IBD). Other models of direct injury to bil
iary epithelia, peribiliary vascular endothelia or portal venous endothelia
indicate that inflammation, chemokines and cytokines can produce diffuse s
clerosis of bile ducts. Models of toxic, infectious or intra-luminal injury
of the biliary tract also exhibit focal biliary sclerosis mediated by infl
ammation and cytokines. The histopathology of several models suggests a seq
uence of events beginning with secretion of proinflammatory cytokines by ac
tivated hepatic macrophages followed by peribiliary infiltration with CD4 a
nd CD8 T cells with a T helper I phenotype. These results strongly suggest
co-ordinated, pathogenetic roles for both the innate and adaptive immune re
sponses. However, the stimuli that initiate and perpetuate peribiliary fibr
osis remain unknown. Interestingly, several models are also associated with
the development of anti-neutrophil cytoplasmic antibodies that react in a
perinuclear and cytoplasmic pattern similar to that observed in patients wi
th ulcerative colitis and/or PSC. Finally, models of extra-hepatic biliary
obstruction continue to provide important information about the pathogenesi
s of portal fibrosis and secondary biliary cirrhosis that occurs in PSC and
other diseases with obstruction of bile flow. Future studies in either exi
sting or new animal models should advance our understanding of the pathogen
esis of PSC, the major prerequisite for the development of effective therap
ies.