Induction of Tolerogenic Dendritic Cells by NF-κB Blockade and Fcγ Receptor Modulation
Autoimmune diseases develop as a result of an unbalanced adaptive immunity that targets self-antigens and causes destruction of healthy host tissues. Maintenance of peripheral immune tolerance to self- antigens is mainly mediated by dendritic cells (DCs), professional antigen-presenting cells that modulate the activation of T cells. Due to their key role as regulators of adaptive immunity, identification of means of enhancing DC tolerogenic capacity and therapeutic potential is a priority goal to reduce autoimmune disease burden in an antigen-specific manner. Our findings suggest novel approaches to enhance DC capacity to induce self-tolerance and reduce the severity of autoimmune disorders. Specifically, we have shown, both in vitro and in vivo, that NF-κB blockade on DCs by andrographolide or rosiglitazone can significantly enhance the tolerogenic capacity of DCs. Furthermore, we have observed that expression ratio of the activating FcγRIII or the inhibitory FcγRIIb is determinant for the tolerogenic potential of DCs. In this chapter, we describe the procedures to produce tolerogenic DCs and explain the potential therapeutic use of two NF-κB inhibitors for the treatment of autoimmune disease models, such as experimental autoimmune encephalomyelitis (EAE) and systemic lupus erythematosus (SLE) in mice. Therefore, our studies support the notion that FcγRs and NF-κB can be considered as pharmacological targets to increase the capacity of DCs to induce or restore self-tolerance and decrease inflammatory damage to self-tissues.
Key wordsDendritic cells NF-κB Andrographolide Rosiglitazone Fcγ receptors EAE SLE
Authors would like to thank all the trainees who contributed to the articles from our group cited in this publication. This work was supported by Grants FONDECYT 1070352 and 1085281 and Millennium Nucleus on Immunology and Immunotherapy (P07/088-F)
- 7.Iruretagoyena, M. I., Sepulveda, S. E., Lezana, J. P., Hermoso, M., Bronfman, M., Gutierrez, M. A., Jacobelli, S. H., and Kalergis, A. M. (2006) Inhibition of nuclear factor-kappa B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis, J Pharmacol Exp Ther 318, 59–67.PubMedCrossRefGoogle Scholar
- 8.Kalergis, A. M., Iruretagoyena, M. I., Barrientos, M. J., González, P. A., Herrada, A. A., Leiva, E. D., Gutiérrez, M. A., Riedel, C. A., Bueno, S. A., and Jacobelli, S. H. (2009) Modulation of nuclear factor-κB activity can influence the susceptibility to systemic lupus erythematosus. Immunology 128, e306–e314.PubMedCrossRefGoogle Scholar
- 9.Iruretagoyena, M. I., Tobar, J. A., Gonzalez, P. A., Sepulveda, S. E., Figueroa, C. A., Burgos, R. A., Hancke, J. L., and Kalergis, A. M. (2005) Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse, J Pharmacol Exp Ther 312, 366–372.PubMedCrossRefGoogle Scholar