These authors contributed equally to this work.
Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice†
Article first published online: 22 APR 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 53, Issue 5, pages 1455–1467, May 2011
How to Cite
Yan, J., Jie, Z., Hou, L., Wanderley, J. L., Soong, L., Gupta, S., Qiu, S., Chan, T. and Sun, J. (2011), Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice. Hepatology, 53: 1455–1467. doi: 10.1002/hep.24270
Potential conflict of interest: Nothing to report.
- Issue published online: 22 APR 2011
- Article first published online: 22 APR 2011
- Accepted manuscript online: 28 FEB 2011 02:49PM EST
- Manuscript Accepted: 14 FEB 2011
- Manuscript Received: 26 APR 2010
- This work was supported by the National Institutes of Health (grant AI69142). Joao L. Wanderley was supported in part by the National Research Council of Brazil (scholarship 201219/2008-5)
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. (Hepatology 2011;)