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Abstract

Apoptotic cells mediate the development of tolerogenic dendritic cells (DC) and thus facilitate the induction and maintenance of peripheral tolerance. Our group investigated the influence of apoptotic cells on DC and identified the cell surface exposure of the evolutionary conserved annexin core domain (Anx) as a specific signal which antagonises Toll-like receptor (TLR) signalling. This study examined whether the tolerogenic capacity of Anx can be exploited to downregulate antigen-specific immune responses to the model antigen ovalbumin (Ova). The treatment of bone marrow-derived dendritic cells (BMDC) with soluble Anx prior to Ova administration or the treatment with beads harbouring Anx as well as Ova attenuated the response of Ova-specific OT-II Tcells. The co-culture of treated DC and Tcells resulted in an anergy-like phenotype characterised by reduced proliferation and cytokine secretion. The anti-inflammatory effects of Anx are mediated through DC by yet unknown mechanisms. Anx did not lead to the tolerogenic DC phenotype described to be induced by apoptotic cells and also the previously reported suppression of anti-inflammatory cytokines by Anx was dispensable for the effect on Tcells. However, this study revealed enhanced production od reactive oxygen species (ROS) in BMDC in response to Anx which might affect the DC/Tcell interactions. Although the underlying mechanisms remain to be elucidated, this study demonstrates that Anx can be used as a tool to generate a particle-based antigen delivery system that promotes antigen-specific immunosuppression. Such Anx-particles may be a new therapeutic approach for the treatment of autoimmune disease.