High-efficiency blockade of IFNα- induced dendritic cell differentiation through inhibition of the immuno-proteasome

High systemic levels of type-I Interferons (IFN) support autoimmunity, in part through the induction of inflammatory dendritic cells (DC). The purpose of this study was to compare ONX 0914, a next-generation selective immunoprotea-some inhibitor, to Bortezomib (BTZ), the first registered general proteasome inhibitor, in its ability to block differentiation of inflammatory DC from mono-cytes, induced by either IL-4 (IL-4 DC) or IFN-α (IFN-DC). While ONX 0914 and BTZ were equally effective at inhibiting differentiation and maturation of both DC types, development of IFN-DC was more profoundly affected, in keeping with their higher relative immunoproteasome content. Indeed, our results show that immunoproteasome inhibition completely abrogates IFN-DC differentiation and their ability to induce pro-inflammatory T cells. We conclude that selective immunoproteasome inhibition by ONX 0914 blocks inflammatory DC development with equal efficacy to BTZ and may present a more viable immu-nosuppressive therapy option for autoimmune disorders with putatively fewer side effects.