7D). Thus, in vivo infusion with DC-FcγRIIb could protect MRL/lpr mice from obvious nephritis injuries. Finally, in vivo administration of DC-FcγRIIb, before (4-wk-old) or after (10-wk-old) the onset of clinic lupus, was found to be able to significantly prolong the survival of MRL/lpr mice, whereas MRL/lpr mice receiving DC-GFP or DCs all died by 40 wk (Fig. 7E). Thus, in vivo administration of DC-FcγRIIb selleck compound could protect MRL/lpr mice from lupus progression, both preventively and therapeutically. SLE is a progressive systemic autoimmune disease, for which current therapy relies largely on long-term suppression of the immune system. We
here provide a short-term treatment regimen to attenuate lupus progression. Single infusion of DC-FcγRIIb, either before or after the onset of clinic lupus, into lupus-prone mice exerts a significant protection from lupus progression. The presence of large amounts of circulating IC in SLE may be potent stimulator for DCs. However, Alectinib order for DC-FcγRIIb, these IC might become potent inhibitor of DC maturation through binding to the preferentially expressed FcγRIIb. FcγRIIb-mediated negative signal contributes to the maintenance of immature/tolerogenic property of DCs. The consequence of this event results in suppression of antigen-specific
T-cell responses and thereby inhibition of B-cell responses, furthermore reducing the generation of autoreactive T cells and autoantibodies. It has been previously reported that decreased FcγRIIb expression is associated with the progression of lupus;
it would therefore make sense that artificial enhancement of the inhibitory FcγRIIb expression on some cell types could possibly provide an efficient approach for the treatment of lupus. In addition to the maintenance of DC tolerogenecity, IC also induce massive PGE2 production from DCs and more PGE2 from DC-FcγRIIb. PGE2 might play a protective role in autoimmune responses via directly inhibiting both CD4+ and CD8+ T-cell responses, inducing Foxp3+ Treg differentiation, suppressing B-cell activation and Ig production 28–32. Moreover, PGE2 Cobimetinib may be also responsible for the inhibition of TLR-induced DC maturation because PGE2-triggered signal is involved in the downregulation of TLR4 expression 27. It is worth investigating whether PGE2 also contributes to inhibition of TLR7 and TLR9 expression, because natural activators of TLR9 and TLR7 can be found in the blood of lupus patients. FcγRIIb seems to be a redundant receptor to mediate PGE2 production, because FcγRIIb−/− DCs can also produce certain amount of PGE2 although much less than that produced by WT DCs in response to stimuli. We found that DCs express more FcγRIIa than FcγRIIb (Supporting Information Fig. 5), suggesting that other activating FcγRs might contribute to the production of PGE2 by IC. Once pretreated with IC and then triggered with TLR-ligands, FcγRIIb−/− DCs could secrete certain level of PGE2.