Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice

S. Wirth, L. G. Guidotti, K. Ando, H. J. Schlicht, F. V. Chisari

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Abstract

Hepatitis B virus (HBV) transgenic mice containing the HBV envelope open reading frame under the transcriptional control of the mouse albumin promoter express hepatitis B surface Ag (HBsAg) in all of their hepatocytes and secrete HBsAg (10 to 40 ng/ml) into the circulation. Because these transgenic mice show no signs of spontaneous liver cell injury or autoimmunity toward the viral (self-) Ag, we asked whether the state of self-tolerance could be reversed by the induction of an acute necroinflammatory liver disease or by immunization with HBV envelope proteins, with the aim of creating a transgenic model for chronic, immune-mediated hepatitis. Our studies indicate that repetitive administration of bacterial LPS, IFN-γ, or HBsAg-specific CTL, all of which were previously shown to cause liver cell injury and inflammation, does not break tolerance at the T or B cell level, suggesting that the intrahepatic lymphomononuclear cell infiltrate induced by these agents consists of HBsAg-nonspecific cells. The adoptive transfer of HBsAg- primed nontransgenic CD4+ T cells into transgenic mice did not induce anti- HBs autoantibody production by transgenic B cells, even though transgenic B cells were fully responsive to immunization with HBsAg when appropriate T cell help was provided in a nontransgenic environment. Immunization of transgenic mice with purified HBsAg in CFA and repetitive infection with rHBV envelope vaccinia virus led to production of T cell-dependent anti-HBs autoantibodies that cleared HBsAg from the serum, but not to activation of HBsAg-specific CTL. We conclude that HBV envelope transgenic mice are largely tolerant to the transgene product at the T cell but not at the B cell level, and that the activation of an anti-HBs response was not sufficient to induce an autoimmune liver disease in this HBV envelope transgenic mouse model.

Original languageEnglish
Pages (from-to)2504-2515
Number of pages12
JournalJournal of Immunology
Volume154
Issue number5
Publication statusPublished - 1995

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Hepatitis B
Hepatitis B virus
Autoantibodies
Transgenic Mice
Autoimmune Diseases
Liver Diseases
T-Lymphocytes
B-Lymphocytes
Immunization
Viral Envelope Proteins
Self Tolerance
Adoptive Transfer
Vaccinia virus
Liver
Wounds and Injuries
Autoimmunity
Transgenes
Hepatitis
Open Reading Frames
Hepatocytes

ASJC Scopus subject areas

  • Immunology

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Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice. / Wirth, S.; Guidotti, L. G.; Ando, K.; Schlicht, H. J.; Chisari, F. V.

In: Journal of Immunology, Vol. 154, No. 5, 1995, p. 2504-2515.

Research output: Contribution to journalArticle

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