title: Calcineurin inhibitors block MHC-restricted antigen presentation in vivo.
abstract: APCs, like T cells, are affected by calcineurin inhibitors. In this study, we show that calcineurin inhibitors efficiently block MHC-restricted exogenous Ag presentation in vivo. Mice were injected with clinical doses of tacrolimus (FK-506) followed by soluble OVA, and dendritic cells (DCs) were isolated from lymph nodes and spleens. The efficacy of OVA peptide presentation by DCs was evaluated using OVA-specific CD8 and CD4 T cells. Tacrolimus inhibited both class I- and class II-restricted DC presentation of OVA to T cells. Tacrolimus also inhibited both class I- and class II-restricted presentation of OVA in peritoneal macrophages isolated from mice injected with tacrolimus followed by soluble OVA. Tacrolimus-treated peritoneal macrophages, however, were able to present synthetic OVA peptide, SIINFEKL. Inclusion of cyclosporine A to biodegradable microspheres containing OVA greatly reduced their capacity to induce OVA-specific CTL response in mice. These findings provide novel insight into the mode of action of calcineurin inhibitors and have important implications for clinical immunosuppression regimens.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Lee
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Lee
authors.forename: Sun-A
authors.initials: SA
authors.lastname: Im
authors.forename: Sun-Im
authors.initials: SI
authors.lastname: Park
authors.forename: Ki-Hyang
authors.initials: KH
authors.lastname: Kim
authors.forename: Turmunkh
authors.initials: T
authors.lastname: Gerelchuluun
authors.forename: Sukgil
authors.initials: S
authors.lastname: Song
authors.forename: Kyungjae
authors.initials: K
authors.lastname: Kim
authors.forename: Chong-Kil
authors.initials: CK
authors.lastname: Lee
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects* / Q000276:immunology*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D065095:Calcineurin Inhibitors; D006649:Histocompatibility Antigens; D016572:Cyclosporine; D010047:Ovalbumin; D019703:Calcineurin; D016559:Tacrolimus