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Am J Physiol Gastrointest Liver Physiol (December 4, 2002). doi:10.1152/ajpgi.00286.2002
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Articles in PresS, published online ahead of print December 4, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00286.2002
Submitted on July 16, 2002
Accepted on November 20, 2002

Impairment of TGF-{beta} signaling in T-cells increases susceptibility to Experimental Autoimmune Hepatitis in mice

Christoph Schramm1, Martina Protschka1, Heinz. -H. Kohler2, Jurgen Podlech3, Mathias J. Reddehase3, Peter Schirmacher4, Peter R. Galle1, Ansgar W. Lohse1, and Manfred Blessing1*

1 Department of Medicine, Department of Pathology, Johannes Gutenberg-University, Mainz, Germany
2 Department of Medicine, Section Pathophysiology, Johannes Gutenberg-University, Mainz, Germany
3 Department of Virology, Johannes Gutenberg-University, Mainz, Germany
4 Department of Pathology, University of Cologne, Cologne, Germany

* To whom correspondence should be addressed. E-mail: blessing{at}mail.uni-mainz.de.

In Autoimmune Hepatitis strong TGF{beta}1 expression is found in the inflamed liver. TGF{beta} overexpression may be part of a regulatory immune response attempting to suppress autoreactive T-cells. To test this hypothesis, we determined whether impairment of TGF{beta} signaling in T-cells leads to increased susceptibility to Experimental Autoimmune Hepatitis. Transgenic mice of strain FVB/N were generated expressing a dominant negative TGF{beta} type II receptor in T-cells under the control of the human CD2 promoter/locus control region. Upon induction of Experimental Autoimmune Hepatitis, transgenic mice showed markedly increased portal and periportal leucocytic infiltrations with hepatocellular necroses compared to wild-type mice (median histologic score: 1.8 ± 0.26 vs 0.75 ± 0.09 in wild-type mice, p<0.01). Increased IFN{gamma} production (118 vs 45 ng/ml) and less IL-4 production (341 vs 1256 pg/ml) by mononuclear cells isolated from transgenic livers was seen. Impairment of TGF{beta} signaling in T-cells therefore leads to increased susceptibility to Experimental Autoimmune Hepatitis in mice. This suggests an important role for TGF{beta} in immune homeostasis in the liver and may teleologically explain TGF{beta} upregulation in response to T-cell mediated liver injury.




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