IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice.
The liver appears to play an important role in immunological tolerance, for example, during allo-transplantation. We investigated tolerance mechanisms in the model of concanavalin A (ConA)-induced immune-mediated liver injury in mice. We found that a single injection of a sublethal ConA dose to C57BL/6 mice induced tolerance toward ConA-induced liver damage within 8 days. This tolerogenic state was characterized by suppression of the typical Th1 response in this model and increased IL-10 production. Tolerance induction was fully reversible in IL-10 -/- mice and after blockade of IL-10 responses by anti-IL10R antibody. Co-cultures of CD4+CD25+ regulatory T cells (T(reg)s) and CD4+CD25- responder cells revealed T(reg) from ConA-tolerant mice being more effective in suppressing polyclonal T cell responses than T(reg) from control mice. Moreover, T(reg) from tolerant but not from control mice were able to augment in vitro IL-10 expression. Depletion by anti-CD25 monoclonal antibody (MAb) indicated a functional role of T(reg)s in ConA tolerance in vivo. Cell depletion studies revealed T(reg)S and Kupffer cells (KC) to be crucial for IL-10 expression in ConA tolerance. Studies with CD1d -/- mice lacking natural killer T (NKT) cells disclosed these cells as irrelevant for the tolerogenic effect. Finally, cellular immune therapy with CD4+CD25+ cells prevented ConA-induced liver injury, with higher protection by Treg from ConA-tolerized mice.


CONCLUSIONS
The immunosuppressive cytokine IL-10 is crucial for tolerance induction in ConA hepatitis and is mainly expressed by CD4+CD25+ T(reg) and KC. Moreover, T(reg)s exhibit therapeutic potential against immune-mediated liver injury.
Erhardt
Annette
A
Institute of Experimental and Clinical Pharmacology and Toxicology, University ofErlangen-Nuremberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
Biburger
Markus
M
Papadopoulos
Thomas
T
Tiegs
Gisa
G
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D003208:Concanavalin A / Q000009:adverse effects*; D004361:Drug Tolerance / Q000502:physiology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007728:Kupffer Cells / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000009:adverse effects*; D012333:RNA, Messenger / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*
D015704:CD4 Antigens; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008934:Mitogens; D012333:RNA, Messenger; D003208:Concanavalin A; D016753:Interleukin-10