title: Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets.
abstract: 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-alpha (IFN-alpha) 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-gamma-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 immunosuppression by CsA.
authors.affiliation: First Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka 570-8506, Japan.
authors.forename: Kenichirou
authors.initials: K
authors.lastname: Tajima
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Amakawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ito
authors.forename: Michihiko
authors.initials: M
authors.lastname: Miyaji
authors.forename: Masashi
authors.initials: M
authors.lastname: Takebayashi
authors.forename: Shirou
authors.initials: S
authors.lastname: Fukuhara
mesh_terms: D039521:CD11c Antigen / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D039521:CD11c Antigen; D016207:Cytokines; D007166:Immunosuppressive Agents; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D016572:Cyclosporine