Abstract
Tolerogenic dendritic cells (DCs) have emerged as relevant clinical targets for the treatment of multiple sclerosis and other autoimmune disorders. However, the pathways essential for conferring the tolerizing DC phenotype and optimal methods for their induction remain an intense area of research. Triterpenoids are a class of small molecules with potent immunomodulatory activity linked to activation of Nrf2 target genes, and can also suppress the manifestations of experimental autoimmune encephalomyelitis (EAE). Here we demonstrate that DCs are a principal target of the immune modulating activity of triterpenoids in the context of EAE. Exposure of DCs to the new class of triterpenoid CDDO-DFPA (RTA-408) results in the induction of HO-1, TGF-β, and IL-10, as well as the repression of NF-κB, EDN-1 and pro-inflammatory cytokines IL-6, IL-12, and TNFα. CDDO-DFPA exposed DCs retained expression of surface ligands and capacity for antigen uptake but were impaired to induce Th1 and Th17 cells. TGF-β was identified as the factor mediating suppression of T cell proliferation by CDDO-DFPA pretreated DCs, which failed to passively induce EAE. These findings demonstrate the potential therapeutic utility of CDDO-DFPA in the treatment and prevention of autoimmune disorders, and its capacity to induce tolerance via modulation of the DC phenotype.
Highlights
Antigen-presenting cells (APCs) or dendritic cells (DCs) are central players in the development and maintenance of immunity and tolerance[1,2,3]
We show the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid-difluoro-propyl-amide, (CDDO-DFPA, RTA-408) induced a profile of DC gene expression characterized by the induction of mediators of a tolerogenic phenotype including heme oxygenase-1 (HO-1), TGF-β and IL-10, without altering DC antigen uptake or expression of cell surface costimulatory molecules
We previously reported the therapeutic utility of various derivatives of the synthetic triterpenoid CDDO in EAE32
Summary
Antigen-presenting cells (APCs) or dendritic cells (DCs) are central players in the development and maintenance of immunity and tolerance[1,2,3]. The suppression of carcinogenesis has been linked to inhibition of pro-inflammatory mediators such as nuclear factor kappa B (NF-κB) and Stat[325], to the induction of tumor suppressor pathways regulated by the prostaglandin degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and by TGF-β26, and through potent transcriptional repression of inducible nitric oxide synthase (iNOS)[27]. These activities predict the potential utility of triterpenoids in the treatment and prevention of autoimmune and inflammatory disorders. The data presented here suggest CDDO-DFPA and related triterpenoids may prove useful for induction of TolDCs, including the ex-vivo expansion of autologous TolDCs for therapeutic application
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