title: Dendritic cells loaded with FK506 kill T cells in an antigen-specific manner and prevent autoimmunity in vivo.
abstract: FK506 (Tacrolimus) is a potent inhibitor of calcineurin that blocks IL2 production and is widely used to prevent transplant rejection and treat autoimmunity. FK506 treatment of dendritic cells (FKDC) limits their capacity to stimulate T cell responses. FK506 does not prevent DC survival, maturation, or costimulatory molecule expression, suggesting that the limited capacity of FKDC to stimulate T cells may be due to inhibition of calcineurin signaling in the DC. Instead, we demonstrate that DC inhibit T cells by sequestering FK506 and continuously releasing the drug over several days. T cells encountering FKDC proliferate but fail to upregulate the survival factor bcl-xl and die, and IL2 restores both bcl-xl and survival. In mice, FKDC act in an antigen-specific manner to inhibit T-cell mediated autoimmune arthritis. This establishes that DCs can act as a cellular drug delivery system to target antigen specific T cells.DOI:http://dx.doi.org/10.7554/eLife.00105.001.
authors: Laboratory of Molecular Neuro-Oncology ,  The Rockefeller University ,  New York ,  United States ; Division of Rheumatology ,  Hospital for Special Surgery ,  New York ,  United States.
authors: Dana E
authors: DE
authors: Orange
authors: Nathalie E
authors: NE
authors: Blachere
authors: John
authors: J
authors: Fak
authors: Salina
authors: S
authors: Parveen
authors: Mayu O
authors: MO
authors: Frank
authors: Margo
authors: M
authors: Herre
authors: Suyan
authors: S
authors: Tian
authors: Sebastien
authors: S
authors: Monette
authors: Robert B
authors: RB
authors: Darnell
mesh_terms: D000818:Animals; D000941:Antigens; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015551:Autoimmunity / Q000187:drug effects*; D065095:Calcineurin Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D024043:Collagen Type II / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D004058:Diffusion; D016503:Drug Delivery Systems; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000941:Antigens; D065095:Calcineurin Inhibitors; D024043:Collagen Type II; D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: FK506; Human; Mouse; autoimmunity; dendritic cells; drug delivery; rheumatoid arthritis
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