Tolerance induction in response to liver inflammation.
OBJECTIVE
The liver plays an important role in immunological tolerance due to its anatomical location, as it links the gastrointestinal tract and the systemic venous circulation. Therefore, immune reactions against dietary or bacterial antigens from the gut have to be avoided. However, immune responses resulting in elimination of harmful hepatotrophic pathogens have to be induced. We investigated mechanisms of tolerance induction in response to liver inflammation in a murine model of immune-mediated liver injury.


METHODS
Liver damage was induced by injection of the plant lectin concanavalin A (ConA). Cytokine levels were measured in plasma and liver tissue. The frequencies of intrahepatic and splenic cell subsets were measured by FACS analyses.


RESULTS
ConA hepatitis was mediated by activation of CD4+ T cells, NKT cells and Kupffer cells releasing IFN-gamma and TNF-alpha. Tolerance developed towards ConA rechallenge within 8 days, lasted for several weeks and was characterized by significantly reduced plasma transaminase activities, decreased Th1/Th17 responses and an increased IL-10 release, the latter being produced by CD4+CD25+FoxP3+ regulatory T cells and Kupffer cells. Moreover, regulatory T cells from ConA-tolerant mice displayed a higher immunosuppressive potential in vitro and in vivo compared to those from non-tolerant animals. Interestingly, ConA hepatitis was aggravated in CCR5(-/-) and CXCR3(-/-) mice.


CONCLUSIONS
These results suggest that ConA tolerance is mediated by induced IL10+ regulatory T cells, probably trafficking into the liver depending on the IFN-gamma-inducible chemokine receptors CCR5 and CXCR3.
Erhardt
Annette
A
Institute of Experimental Immunology and Hepatology, Center of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Tiegs
Gisa
G
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D003208:Concanavalin A / Q000276:immunology; D004195:Disease Models, Animal; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000628:therapy; D007108:Immune Tolerance; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D019707:Receptors, Chemokine / Q000276:immunology
D018925:Chemokines; D019707:Receptors, Chemokine; D003208:Concanavalin A