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IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A–induced liver injury in mice

✍ Scribed by Annette Erhardt; Markus Biburger; Thomas Papadopoulos; Gisa Tiegs

Publisher
John Wiley and Sons
Year
2007
Tongue
English
Weight
567 KB
Volume
45
Category
Article
ISSN
0270-9139

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✦ Synopsis

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 T reg from ConA-tolerized mice. Conclusion: 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.

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