Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis

Ya Hui Chuang, Zhe Xiong Lian, Guo Xiang Yang, Shang An Shu, Yuki Moritoki, William M. Ridgway, Aftab A. Ansari, Mitchell Kronenberg, Richard A. Flavell, Bin Gao, M. Eric Gershwin

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Abstract

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NKT cells in our transforming growth factor β (TGF-β) receptor II dominant-negative (dnTGFβRII) mouse model of PBC. We generated CD1d-/- and CD1d+/- dnTGFβRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFβRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d -/-dnTGFβRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significandy decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d+/-dnTGFβRII mice. Interestingly, there was a significant increase in the production of interferon-γ in hepatic CD1d-restricted NKT cells activated by α-galactosylceramide in young but not older dnTGFβRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGFβRII mice are a critical factor in liver injury.

Original languageEnglish (US)
Pages (from-to)571-580
Number of pages10
JournalHepatology
Volume47
Issue number2
DOIs
StatePublished - Feb 2008

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Natural Killer T-Cells
Growth Factor Receptors
Biliary Liver Cirrhosis
Transforming Growth Factors
Liver
Wounds and Injuries
Galactosylceramides
Intrahepatic Bile Ducts
Cholangitis
Interferons
Autoimmune Diseases
Liver Diseases
Hepatocytes
Lymphocytes
Inflammation
Antibodies

ASJC Scopus subject areas

  • Hepatology

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Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis. / Chuang, Ya Hui; Lian, Zhe Xiong; Yang, Guo Xiang; Shu, Shang An; Moritoki, Yuki; Ridgway, William M.; Ansari, Aftab A.; Kronenberg, Mitchell; Flavell, Richard A.; Gao, Bin; Gershwin, M. Eric.

In: Hepatology, Vol. 47, No. 2, 02.2008, p. 571-580.

Research output: Contribution to journalArticle

Chuang, YH, Lian, ZX, Yang, GX, Shu, SA, Moritoki, Y, Ridgway, WM, Ansari, AA, Kronenberg, M, Flavell, RA, Gao, B & Gershwin, ME 2008, 'Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis', Hepatology, vol. 47, no. 2, pp. 571-580. https://doi.org/10.1002/hep.22052
Chuang, Ya Hui ; Lian, Zhe Xiong ; Yang, Guo Xiang ; Shu, Shang An ; Moritoki, Yuki ; Ridgway, William M. ; Ansari, Aftab A. ; Kronenberg, Mitchell ; Flavell, Richard A. ; Gao, Bin ; Gershwin, M. Eric. / Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis. In: Hepatology. 2008 ; Vol. 47, No. 2. pp. 571-580.
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abstract = "Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NKT cells in our transforming growth factor β (TGF-β) receptor II dominant-negative (dnTGFβRII) mouse model of PBC. We generated CD1d-/- and CD1d+/- dnTGFβRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFβRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d -/-dnTGFβRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significandy decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d+/-dnTGFβRII mice. Interestingly, there was a significant increase in the production of interferon-γ in hepatic CD1d-restricted NKT cells activated by α-galactosylceramide in young but not older dnTGFβRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGFβRII mice are a critical factor in liver injury.",
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AU - Chuang, Ya Hui

AU - Lian, Zhe Xiong

AU - Yang, Guo Xiang

AU - Shu, Shang An

AU - Moritoki, Yuki

AU - Ridgway, William M.

AU - Ansari, Aftab A.

AU - Kronenberg, Mitchell

AU - Flavell, Richard A.

AU - Gao, Bin

AU - Gershwin, M. Eric

PY - 2008/2

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AB - Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NKT cells in our transforming growth factor β (TGF-β) receptor II dominant-negative (dnTGFβRII) mouse model of PBC. We generated CD1d-/- and CD1d+/- dnTGFβRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFβRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d -/-dnTGFβRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significandy decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d+/-dnTGFβRII mice. Interestingly, there was a significant increase in the production of interferon-γ in hepatic CD1d-restricted NKT cells activated by α-galactosylceramide in young but not older dnTGFβRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGFβRII mice are a critical factor in liver injury.

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