UNLABELLED: 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.
UNLABELLED: 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.
Authors: Jan-Eric Turner; Hans-Joachim Paust; Oliver M Steinmetz; Anett Peters; Jan-Hendrik Riedel; Annette Erhardt; Claudia Wegscheid; Joachim Velden; Susanne Fehr; Hans-Willi Mittrücker; Gisa Tiegs; Rolf A K Stahl; Ulf Panzer Journal: J Am Soc Nephrol Date: 2010-03-18 Impact factor: 10.121
Authors: Anil Dangi; Tina L Sumpter; Shoko Kimura; Donna B Stolz; Noriko Murase; Giorgio Raimondi; Yoram Vodovotz; Chao Huang; Angus W Thomson; Chandrashekhar R Gandhi Journal: J Immunol Date: 2012-03-16 Impact factor: 5.422