title: Low-dose immunosuppression by cyclosporine operating via antigen-presenting dendritic cells.
abstract: The inhibitory effect of cyclosporine on the stimulation of lymphocytes was tested in 20 microliters hanging drop cultures. Cells were stimulated by concanavalin A, or by allogeneic dendritic cells in a mixed leukocyte culture (MLC). Significant inhibition of lymphocyte proliferation was obtained with low concentrations of CsA (10(-9)-10(-7) micrograms/ml) in addition to the well-documented, dose-dependent inhibition at concentrations greater than or equal to 10(-1) micrograms/ml. Intermediate doses (10(-6)-10(-2) micrograms/ml) caused little inhibition. To establish whether the CsA was acting on the antigen-presenting cells or on the responding T cells, each population was pulsed with CsA before adding to the MLC. Higher doses of CsA were required to cause inhibition using this short-term pretreatment rather than continuous presence of CsA; however, when DC were pulsed with CsA, biphasic effects of the drug were seen. The time of DC pretreatment with 1 microgram/ml CsA was varied, and inhibition was seen after 1-3 hr and 16-24 hr pretreatment but not at intermediate time points. Similarly, a biphasic dose-response developed when DC-pretreatment time was fixed (2 hr) and drug concentration was varied. By contrast, on pulsing responder lymphocytes with CsA there was a biphasic effect in some experiments, but more often a single dose-dependent inhibition occurred, particularly when DC were removed from the responder cells. Major dose-dependent inhibitory effects of CsA may therefore act on both antigen-presenting DC and on lymphocytes, but this work reveals an additional low-dose inhibition that can operate via DC.
authors.affiliation: Antigen Presentation Research Group, MRC Clinical Research Centre, Harrow, England.
authors.forename: M S
authors.initials: MS
authors.lastname: Roberts
authors.forename: S C
authors.initials: SC
authors.lastname: Knight
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA
chemical_list: D003524:Cyclosporins