IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice.
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IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. / Erhardt, Annette; Biburger, Markus; Papadopoulos, Thomas; Tiegs, Gisa.
In: HEPATOLOGY, Vol. 45, No. 2, 2, 2007, p. 475-485.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice.
AU - Erhardt, Annette
AU - Biburger, Markus
AU - Papadopoulos, Thomas
AU - Tiegs, Gisa
PY - 2007
Y1 - 2007
N2 - 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. 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.
AB - 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. 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 45
SP - 475
EP - 485
JO - HEPATOLOGY
JF - HEPATOLOGY
SN - 0270-9139
IS - 2
M1 - 2
ER -