The novel cyclophilin-binding drug sanglifehrin A specifically affects antigen uptake receptor expression and endocytic capacity of human dendritic cells

Abstract

Sanglifehrin A (SFA) is a recently developed immunosuppressant that belongs to the family of immunophilin-binding ligands. SFA is a cyclophilin A-binding immunosuppressive drug with a novel, but unidentified, mechanism of action. Several reports exist about the effect of SFA on T cells, but its effect on the initiators of the immune response, i.e., dendritic cells (DCs), is relatively unknown. Therefore, we examined the effect of SFA on the differentiation and function of human monocyte-derived DCs. Unlike the well-known cyclophilin A-binding immunosuppressant cyclosporin A, which did not affect DC phenotype, differentiation of DCs in the presence of SFA resulted in CD14-CD1a DCs with normal DC morphology, viability, and a proper capacity to activate allogeneic T cells. However, DCs generated in the presence of SFA demonstrated reduced macropinocytosis and lectin-mediated endocytosis, which was in line with a decreased expression of C-type lectins, including mannose receptor, C1qRP, DC-ASGPR, and especially, DC-SIGN. In contrast, FcalphaRI (CD89) and FcgammaRII (CD32) were increased by SFA. The explicit effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among immunophilin-binding immunosuppressive drugs.