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Hepatic T Cell Tolerance Induction in An Inflammatory Environment.

Janine Dywicki1, Fatih Noyan, Ana Clara Misslitz

  • 1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Digestive Diseases (Basel, Switzerland)
|October 12, 2017
PubMed
Summary

Genetic susceptibility is crucial for breaking tolerance in autoimmune hepatitis (AIH). Even with high autoreactive T cells and inflammation, tolerance persists, suggesting anergy plays a key role in AIH development.

Keywords:
(Experimental) autoimmune hepatitisAdenovirusAutoreactive T cellsHemagglutininHepatic toleranceTransgenic autoantigens

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Area of Science:

  • Immunology
  • Hepatology
  • Autoimmunity

Background:

  • Autoimmune hepatitis (AIH) development involves genetic predisposition and environmental factors.
  • Studying liver-specific T cells in experimental AIH is challenging due to low autoreactive T cell precursor frequency.

Purpose of the Study:

  • To establish a novel mouse model for studying autoimmune hepatitis (AIH) by expressing a model antigen (hemagglutinin) in hepatocytes.
  • To investigate the mechanisms of tolerance breakdown and T cell responses in the context of AIH.

Main Methods:

  • Hepatocyte-specific antigen expression was induced in Rosa26-HA mice using adenovirus-Cre (Ad-Cre).
  • Autoreactive T cells (HA-specific Cl4-TCR and 6.5-TCR) were adoptively transferred or generated via TCR transgenic crosses.
  • Tolerance breakdown and T cell proliferation were assessed following antigen expression and adenoviral infection.

Main Results:

  • Hepatocytes successfully mimicked altered-self neoantigen generation upon Ad-Cre administration.
  • Neither adoptive transfer nor high precursor frequency of autoreactive T cells broke hepatic tolerance.
  • Limited proliferation of autoreactive T cells, despite antigen presence and inflammation, suggests anergy.

Conclusions:

  • The developed model highlights the critical role of genetic susceptibility in overcoming tolerance to hepatic autoantigens.
  • Anergy appears to be a significant mechanism maintaining tolerance in the liver, even during inflammation.