Abstracts (complete list) - Wissenschaft Online

Annette Erhardt, Markus Biburger, Gisa Tiegs
IL-10 AND REGULATORY T CELLS – THE MAIN MEDIATORS OF
IMMUNOLOGICAL TOLERANCE AGAINST CONCANAVALIN A
Injection of the plant lectin Concanavalin A (ConA) induces pronounced T- and NKT-cell
activation followed by the onset of acute liver injury. ConA hepatitis has often been
described as a murine model for immune-mediated hepatitis in humans. Recently, we
have shown that ConA pretreated mice developed tolerance against ConA rechallenge
within 8 days. Suppression of liver damage upon ConA pretreatment was characterized
by decreased plasma transaminase levels and an anti-inflammatory cytokine response
with increased IL10 production. Tolerance was fully reversed in IL10 KO mice
emphasizing the important role of IL10 during ConA tolerance.
To confirm the relevance of IL10, neutralizing experiments with an anti-IL10R antibody
were performed blocking the binding site of IL10. Antibody injection prior to ConA
pretreatment, imitating IL10 KO mice, or prior to ConA restimulation largely reduced
the tolerogenic effect, suggesting that IL10 participates in long-term differentiation
processes but also acts as short-term immunosuppressive mediator in vivo.
Depletion of regulatory T cells (Tregs) and Kupffer cells in vivo prior to ConA
rechallenge significantly diminished IL10 production, revealing these cells as main
sources of IL10. Accordingly, Tregs isolated from ConA tolerized mice exhibited
significantly enhanced IL10 production after ex vivo restimulation in contrast to control
Tregs. However, in vitro neutralization of IL10 in co-cultures of responder cells and
Tregs failed to reverse the immunosuppressive effect of Tregs from control as well as
from ConA tolerant mice.
In an immuno-therapeutic approach Tregs isolated from tolerized WT mice conferred
significant protection from ConA-induced liver damage in contrast to Tregs from
tolerized IL10 KO mice.
In summary, we demonstrated that ConA tolerance, characterized by both
immunosuppression and protection from liver injury, is mediated by Kupffer cells, Tregs,
and IL10. Hence, ConA tolerance appears to be an appropriate model for evaluation of
therapeutic intervention strategies in complex immuno-regulatory systems.