Received for publication February 21, 2006.
Revised March 29, 2006.
Accepted for publication April 4, 2006.

Inhibition of NF-B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in Experimental Autoimmune Encephalomyelitis

Abstract

Autoimmune disorders develop as a result of deregulated immune responses that target self-antigens and cause destruction of healthy host tissues. Due that dendritic cells (DCs) play an important role in the maintenance of peripheral immune tolerance we are interested in identifying means of enhancing their therapeutic potential in autoimmune diseases. It is thought that during the steady state, DCs are able to anergize potentially harmful T cells bearing TCRs that recognize self-peptide-MHC complexes. The tolerogenic capacity of DCs requires an immature phenotype, which is characterized by a reduced expression of costimulatory molecules. On the contrary, activation of antigen-specific naive T cells is enhanced by DC maturation, a process that involves expression of genes controlled by the transcription factor NF-B. We evaluated the capacity of drugs that inhibit NF-B to enhance the tolerogenic properties of immature DCs in the Experimental Autoimmune Encephalomyelitis (EAE) model. We show that andrographolide, a bicyclic diterpenoid lactone, and rosiglitazone, a PPAR- agonist, were able to interfere with NF-B activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Further, NF-B-blocked DCs had an enhanced tolerogenic capacity and were able to prevent EAE development in mice. The tolerogenic feature was specific for myelin antigens and involved the expansion of regulatory T cells. These data suggest that NF-B blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.

Key words: EAE, T cells, autoimmunity, dendritic cells, mouse, tolerance

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