Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets

摘要

Cyclosporin A (CsA) is a potent immuno-suppressant and is approved for the treatment of various disease conditions. The molecular biological mechanism of CsA has been investigated intensively in T cells and has been shown to involve the intracellular calcineurin pathway. Recently, it was reported that CsA has capacities to affect not only T cells but also antigen-presenting cells such as B cells and dendritic cells (DCs). DCs are a master regulator of immune responses that have an integral capacity to prime naive T cells. In the present study, we investigated the biological effects of CsA on human peripheral blood DC subsets: CD11c⁺ myeloid and CD11c⁻ lymphoid subsets. CsA inhibited the up-regulation of co-stimulatory molecules induced with or without microbial stimuli and CD40L on both CD11c⁺ and CD11c⁻ subsets. In addition, CsA negatively regulated the endocytic activity of CD11c⁺ DC during the immature state. CsA inhibited the interleukin-12 (IL-12) production, but augmented the IL-10 production from the LPS-stimulated CD11c⁺ subset, whereas CsA reduced the interferon-α (IFN-α) production from the CD11c⁻ subset infected with Sendai virus (SV). Both the LPS-stimulated CD11c⁺ subset and SV-infected CD11c⁻ subset preferentially induced the development of IFN-γ-producing T helper-type 1 (Th1) cells. Pretreatment of these DC subsets with CsA inhibited the Th1 skewing. These findings suggested a DC-mediated mechanism of immunosupression by CsA.