Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice

Jiabin Yan, Zuliang Jie, Lifei Hou, Joao L. Wanderley, Lynn Soong, Shalini Gupta, Suimin Qiu, Tehsheng Chan, Jiaren Sun

Research output: Contribution to journalArticle

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Abstract

The healthy adult human liver expresses low levels of major histocompatibility complex class II (MHC II) and undetectable levels of immune costimulatory molecules. However, high levels of MHC II, CD40, and B7 family molecules are expressed in the activated Kupffer cells and hepatocytes of patients with viral hepatitis. The precise role of these molecules in viral clearance and immune-mediated liver injury is not well understood. We hypothesized that parenchymal CD40 expression enhances T cell recruitment and effector functions, which may facilitate viral clearance and alleviate liver injury. To test this hypothesis, we generated novel liver-specific, conditional CD40 transgenic mice, and we challenged them intravenously with a recombinant replication-deficient adenovirus carrying Cre recombinase (AdCre). Wild-type mice infected with AdCre developed a relatively mild course of viral hepatitis and recovered spontaneously. CD40 expression in the livers of transgenic animals, however, resulted in CD80 and CD86 expression. The dysregulation of population dynamics and effector functions of intrahepatic lymphocytes (IHLs) resulted in severe lymphocytic infiltration, apoptosis, necroinflammation, and serum alanine aminotransferase elevations in a dose-dependent fashion. To our surprise, an early expansion and subsequent contraction of IHLs (especially CD8+ and natural killer cells), accompanied by increased granzyme B and interferon-γ production, did not lead to faster viral clearance in CD40 transgenic mice. Conclusion: Our results demonstrate that hepatic CD40 expression does not accelerate adenoviral clearance but rather exacerbates liver injury. This study unveils a previously unknown deleterious effect of hepatic CD40 on adenovirus-induced liver inflammation.

Original languageEnglish (US)
Pages (from-to)1455-1467
Number of pages13
JournalHepatology
Volume53
Issue number5
DOIs
StatePublished - May 2011

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Adenoviridae
Hepatitis
Liver
Major Histocompatibility Complex
Transgenic Mice
Wounds and Injuries
B7 Antigens
Lymphocytes
Granzymes
Genetically Modified Animals
Kupffer Cells
Population Dynamics
Alanine Transaminase
Natural Killer Cells
Interferons
Hepatocytes
Apoptosis
Inflammation
T-Lymphocytes
Serum

ASJC Scopus subject areas

  • Hepatology

Cite this

Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice. / Yan, Jiabin; Jie, Zuliang; Hou, Lifei; Wanderley, Joao L.; Soong, Lynn; Gupta, Shalini; Qiu, Suimin; Chan, Tehsheng; Sun, Jiaren.

In: Hepatology, Vol. 53, No. 5, 05.2011, p. 1455-1467.

Research output: Contribution to journalArticle

Yan, J, Jie, Z, Hou, L, Wanderley, JL, Soong, L, Gupta, S, Qiu, S, Chan, T & Sun, J 2011, 'Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice', Hepatology, vol. 53, no. 5, pp. 1455-1467. https://doi.org/10.1002/hep.24270
Yan, Jiabin ; Jie, Zuliang ; Hou, Lifei ; Wanderley, Joao L. ; Soong, Lynn ; Gupta, Shalini ; Qiu, Suimin ; Chan, Tehsheng ; Sun, Jiaren. / Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice. In: Hepatology. 2011 ; Vol. 53, No. 5. pp. 1455-1467.
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