Immunomodulatory effects of cyclosporin A on human peripheral blood dendritic cell subsets
Kenichirou Tajima,Ryuichi Amakawa,Tomoki Ito,Michihiko Miyaji,Masashi Takebayashi,Shirou Fukuhara +5 more
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TLDR
Findings suggest a DC‐mediated mechanism of immunosupression by CsA on human peripheral blood DC subsets, which has capacities to affect not only T cells but also antigen‐presenting cells such as B cells and dendritic cellsAbstract:
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.read more
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References
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Dendritic cells and the control of immunity
TL;DR: Once a neglected cell type, dendritic cells can now be readily obtained in sufficient quantities to allow molecular and cell biological analysis and the realization that these cells are a powerful tool for manipulating the immune system is realized.
Journal ArticleDOI
Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes
Jun Liu,Jesse D. Farmer,Willam S. Lane,Jeffrey S. Friedman,Irving L. Weissman,Stuart L. Schreiber +5 more
TL;DR: The results suggest that calcineurin is involved in a common step associated with T cell receptor and IgE receptor signaling pathways and that cyclophilin and FKBP mediate the actions of CsA and Fk506 by forming drug-dependent complexes with and altering the activity of calcineURin-calmodulin.
Journal ArticleDOI
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Frederick P. Siegal,Norimitsu Kadowaki,Michael Shodell,Patricia Fitzgerald-Bocarsly,Kokila Shah,Stephen Ho,Svetlana Antonenko,Yong-Jun Liu +7 more
TL;DR: Purified IPCs are here shown to be the CD4(+)CD11c- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge and are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses.
Journal ArticleDOI
Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens.
Norimitsu Kadowaki,Stephen Ho,Svetlana Antonenko,Rene de Waal Malefyt,Robert A. Kastelein,J. Fernando Bazan,Yong-Jun Liu +6 more
TL;DR: The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.
Journal ArticleDOI
The mechanism of action of cyclosporin A and FK506
TL;DR: Recent findings that indicate CsA and FK506 operate as prodrugs are reviewed: they bind endogenous intracellular receptors, the immunophilins, and the resulting complex targets the protein phosphatase, calcineurin, to exert the immunosuppressive effect.