title: Inhibition of nuclear factor-kappa 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. Because 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 steady state, DCs are able to anergize potentially harmful T cells bearing T cell receptors that recognize self-peptide-major histocompatibility 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 nuclear factor (NF)-kappaB. We evaluated the capacity of drugs that inhibit NF-kappaB 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 peroxisome proliferator-activated receptor gamma agonist, were able to interfere with NF-kappaB activation in murine DCs. As a result, treated DCs showed impaired maturation and a reduced capacity to activate antigen-specific T cells. Furthermore, NF-kappaB-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-kappaB blockade is a potential pharmacological approach that can be used to enhance the tolerogenic ability of immature DCs to prevent detrimental autoimmune responses.
authors.affiliation: Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.
authors.forename: Mirentxu I
authors.initials: MI
authors.lastname: Iruretagoyena
authors.forename: Sofía E
authors.initials: SE
authors.lastname: Sepúlveda
authors.forename: J Pablo
authors.initials: JP
authors.lastname: Lezana
authors.forename: Marcela
authors.initials: M
authors.lastname: Hermoso
authors.forename: Miguel
authors.initials: M
authors.lastname: Bronfman
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gutiérrez
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Jacobelli
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000941:Antigens; D016328:NF-kappa B