Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance

McCaughan, Geoffrey W.
Gorrell, Mark D.
Bishop, G. Alex
Abbott, Catherine A.
Shackel, Nicholas A.
McGuinness, Peter H.
Levy, Miriam T.
Sharland, Alexandra F.
Bowen, David G.
Yu, Denise
Slaitini, Loubnah
Church, W. Bret
Napoli, John

Authors' addresses Geoffrey W. McCaughan¹, Mark D. Gorrell¹, G. Alex Bishop¹, Catherine A. Abbott¹, Nicholas A. Shackel¹, Peter H. McGuinness¹, Miriam T. Levy¹, Alexandra F. Sharland¹, David G. Bowen¹, Denise Yu², Loubnah Slaitini³, W. Bret Church⁴, John Napoli⁵, ¹A. W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Centenary Institute of Cancer Medicine and Cell Biology and The University of Sydney, Sydney, Australia. ²Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia. ³Department of Pathology, The University of Sydney, Australia. ⁴Garvan Institute of Medical Research, Sydney, Australia. ⁵Department of Gastroenterology, Royal North Shore Hospital, Sydney, Australia.

Correspondence to: G. W. McCaughan; Centenary Institute of Cancer Medicine and Cell Biology; Locked Bag No. 6; Newtown; NSW 2042; Australia; Fax: 61 2 9565 6101; e-mail: [email protected]

Acknowledgements This research was supported by the National Health and Medical Research Council of Australia and was carried out while all authors except W. B. Church worked at the A. W. Morrow Gastroenterology and Liver Centre.

Immunological Reviews 174:p 172-191, April 2000.

Summary:

The hallmarks of chronic liver diseases are chronic inflammation, cellular damage, regeneration and fibrosis. An appreciation of intrahepatic molecular expression patterns in normal and diseased liver provides clues for understanding pathogenic pathways whilst studies of the structure and function of molecules implicated in liver disease provide insights into their potential as therapeutic targets. We have examined the expression, function, molecular structure and structure-function relationships of type IV dipeptidyl aminopeptidases. In particular, the roles of CD26/DPPIV in T-cell proliferation and chemotaxis and of fibroblast activation protein in human cirrhosis are discussed. We have investigated the pathogenesis of liver disease by characterising patterns of cytokine and growth factor expression in experimental and human cirrhosis. We have quite recently expanded this approach to use differential gene expression analyses to elucidate overall pathways of gene activation and suppression in human cirrhosis. In addition, our detailed molecular and cellular studies of the mechanisms of spontaneous liver transplant tolerance have generated novel insights into this process. This review touches on these diverse aspects of liver function and disease.