The Journal of Experimental Medicine
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Published online 22 November 2004 doi:10.1084/jem.20041035
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 11, 1511-1517
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Brief Definitive Report

 Hepatic Endothelial CCL25 Mediates the Recruitment of CCR9+ Gut-homing Lymphocytes to the Liver in Primary Sclerosing Cholangitis

Bertus Eksteen1, Allister J. Grant1, Alice Miles1, Stuart M. Curbishley1, Patricia F. Lalor1, Stefan G. Hübscher1, Michael Briskin3, Mike Salmon2, and David H. Adams1

1 Liver Research Laboratories, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, England, UK
2 Department of Rheumatology, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, England, UK
3 Millennium Pharmaceuticals Inc., Cambridge, MA 02139

Address correspondence to David H. Adams, Liver Research Laboratories, Institute for Biomedical Research, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TT, England, UK. Phone: 44-121-4158700; Fax: 44-121-4158701; email: d.h.adams{at}bham.ac.uk

Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433–1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.J., P.F. Lalor, M. Salmi, S. Jalkanen, and D.H. Adams. 2002. Lancet. 359:150–157). In support of this, we show that liver-infiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gut-specific chemokine CCL25 that activates {alpha}4ß7 binding to mucosal addressin cell adhesion molecule 1 on the hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD.

Key Words: chemokines • integrins • inflammation • hepatitis • colitis


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