SFA monotherapy did not suppress acute organ allograft rejection supporting the hypothesis that it does not represent a primary T cell inhibitor. Interestingly, in combination with CsA, SFA efficiently promoted long-term allograft survival. Furthermore, in a chronic allograft rejection model, addition of SFA to CsA-treated recipients markedly inhibited chronic rejection compared to animals receiving high dose CsA monotherapy, suggesting that SFA exerted unique immunobiological effects different from DAPT inhibition of calcineurin phosphatases. Current knowledge indicates that SFA represents a novel class of immunophilin-binding metabolite both with respect to chemical structure and functional activity. There is a paucity of knowledge about the immunobiological effects of SFA since each study focused on selected functions or selected aspects with professional antigen presenting cells being either directly or indirectly involved. Systematic studies investigating the effects of SFA are completely lacking. In this report we describe the results of the first systematic analysis of the immunobiological effects of the novel immunophilin-binding agent SFA on human monocyte-derived DC using a combination of genome-wide expression profiling with subsequent confirmation on the protein level and functional in vitro and in vivo assays. Results indicate that SFA represents a novel DC CX-4945 1009820-21-6 chemokine and migration inhibitor. Sanglifehrins represent novel immunosuppressive agents that have been reported to suppress key functions of DCs. We and others have reported that SFA inhibits bioactive IL-12p70 production, macropinocytosis as well as receptor-mediated endocytosis in human and murine DCs. Transplant experiments indicated that addition of SFA to CsA efficiently suppresses graft arteriosclerosis in comparison to CsA monotherapy suggesting that SFA may represent a novel class of immunophilin-binding agents. However, a disadvantage of previous studies is the fact that they have focused on selected molecules or selected functional aspects thereby restricting the possibility to discover novel mechanisms of action. Accordingly, the aim of the present study was to use a systematic genome-wide approach in order to reveal novel immunobiological effects of SFA on human DC. Secondly, identification of molecules being most specifically suppressed by SFA in comparison to the related molecule CsA may help to elucidate the mechanism of action. The results presented here indicate that SFA impairs DCmediated immunity in a so far unrecognized manner that is DC chemokine expression and migration. Importantly, SFA��s inhibitory effects can be demonstrated on two different functional levels such as direct chemokine expression inhibition and subsequent impaired attraction of CD4 helper T cells as wells as DC migration inhibition towards recombinant CCL19. Accordingly, we have found that SFA, in contrast to CsA, does not only inhibit mRNA and protein expression of a number of chemokines, including CCL5, CCL17 and CCL19 but additionally suppresses CD38 mRNA and DC surface expression. Thus, SFA��s effects on DC are unique in direct comparison to the related cyclophilin-binding immunosuppressant CsA. The latter results provide a rationale for the explanation of reduced migration of SFA-exposed moDCs against recombinant CCL19. CD38 has been reported to be required forthe migration of mature DC against recombinant CCL19. Furthermore, CD38 inhibition by SFA provides additional insight into recent reports demonstrating SFA��s capacity to abrogate bioactive IL-12 production in vitro and in vivo.