Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia
Pranavkumar Shivakumar, … , Richard L. Ward, Jorge A. Bezerra
Pranavkumar Shivakumar, … , Richard L. Ward, Jorge A. Bezerra
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):322-329. https://doi.org/10.1172/JCI21153.
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Article Hepatology

Obstruction of extrahepatic bile ducts by lymphocytes is regulated by IFN-γ in experimental biliary atresia

Abstract

The etiology and pathogenesis of bile duct obstruction in children with biliary atresia are largely unknown. We have previously reported that, despite phenotypic heterogeneity, genomic signatures of livers from patients display a proinflammatory phenotype. Here, we address the hypothesis that production of IFN-γ is a key pathogenic mechanism of disease using a mouse model of rotavirus-induced biliary atresia. We found that rotavirus infection of neonatal mice has a unique tropism to bile duct cells, and it triggers a hepatobiliary inflammation by IFN-γ–producing CD4+ and CD8+ lymphocytes. The inflammation is tissue specific, resulting in progressive jaundice, growth failure, and greater than 90% mortality due to obstruction of extrahepatic bile ducts. In this model, the genetic loss of IFN-γ did not alter the onset of jaundice, but it remarkably suppressed the tissue-specific targeting of T lymphocytes and completely prevented the inflammatory and fibrosing obstruction of extrahepatic bile ducts. As a consequence, jaundice resolved, and long-term survival improved to greater than 80%. Notably, administration of recombinant IFN-γ led to recurrence of bile duct obstruction following rotavirus infection of IFN-γ–deficient mice. Thus, IFN-γ–driven obstruction of bile ducts is a key pathogenic mechanism of disease and may constitute a therapeutic target to block disease progression in patients with biliary atresia.

Authors

Pranavkumar Shivakumar, Kathleen M. Campbell, Gregg E. Sabla, Alexander Miethke, Greg Tiao, Monica M. McNeal, Richard L. Ward, Jorge A. Bezerra

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Loss of IFN-γ prevents obstruction of extrahepatic bile ducts. Anatomica...
Loss of IFN-γ prevents obstruction of extrahepatic bile ducts. Anatomical view of the hilum (A–D) of WT Balb/c mice displayed small, edematous gallbladders (*) at 7 and 14 days after RRV challenge, with long- (7 days) or short- (14 days) segment atresia of extrahepatic bile ducts (thin arrows). In contrast, IFN-γ–/– mice displayed gallbladders distended with bile (**) and unobstructed bile ducts (thick arrows). Arrowheads point to arterial vessels that follow extrahepatic bile ducts. Microscopically (E–H), bile ducts of WT Balb/c mice demonstrated lumenal obstruction by inflammatory cells (7 days) and extracellular matrix (14 days). In IFN-γ–/– mice, extrahepatic bile ducts had periductal inflammation and mild epithelial injury, but the lumen remained patent and without accumulation of matrix substrates at 7–14 days. Sections were stained with H&E; magnification, ×200; arrows in (E) and (G) denote obstructed bile ducts.