Sanglifehrin A (SFA) is a novel cyclophilin-binding immunosuppressant with an unknown mechanism of action. IL-12p70 plays a critical role in the pathogenesis of inflammation and autoimmune diseases. We discovered that SFA abrogates bioactive IL-12p70 production by human dendritic cells, the major producers of this cytokine. In direct comparison to the related calcineurin inhibitor cyclosporin A and the mammalian target of rapamycin inhibitor rapamycin, SFA acts uniquely within 1 h to inhibit (80–95%) IL-12p70 production by differentiated dendritic cells. Experiments with Toll-like receptor 3 and 4 ligands show a stimulus-independent suppression. Competitive experiments with a molar excess of cyclosporin A indicate a cyclophilin A-independent blockade of IL-12p70 production. We confirm potent inhibition of IL-12p70 production by SFA using purified human blood DC. Real-time RT-PCR reveals 84–94% suppression of IL-12p40, IL-12p35, and IL-23-specific p19 transcription. These novel insights into the immunosuppressive action of SFA are likely to impact on the clinical use of this agent.
Sanglifehrin A (SFA) is a novel compound with unsurpassed cyclophilin-binding affinity, but relatively low direct antilymphocytic activity. Here, we report the capacity of SFA to selectively inhibit key dendritic cell (DC) functions in vivo and to suppress acute and chronic heart allograft rejection. We show that in vivo, SFA profoundly decreases DC receptor-mediated endocytosis and macropinocytosis and DC-T-cell allostimulatory activity. Furthermore, SFA abrogates >90% of IL-12p70 production in vivo while having no significant effect on IL-10 and TNF-a production. In a rat vascularized heart transplant model, SFA alone did not prevent graft rejection and rejection occurred within 23 days after low-dose CsA, whereas addition of SFA to low-dose CsA promoted long-term graft survival (median survival time >100 days; p = 0.0007). With respect to chronic rejection, SFA + CsA almost completely prevented graft arteriosclerosis compared to animals treated with CsA alone and controls. We propose that SFA represents a novel class of immunophilin-binding immunosuppressants with high activity against DCs and the development of graft vasculopathy in CsAtreated recipients.
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