Calcineurin inhibitors block MHC-restricted antigen presentation in vivo.
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.
Lee
Young-Hee
YH
College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
Lee
Young-Ran
YR
Im
Sun-A
SA
Park
Sun-Im
SI
Kim
Ki-Hyang
KH
Gerelchuluun
Turmunkh
T
Song
Sukgil
S
Kim
Kyungjae
K
Lee
Chong-Kil
CK
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
D065095:Calcineurin Inhibitors; D006649:Histocompatibility Antigens; D016572:Cyclosporine; D010047:Ovalbumin; D019703:Calcineurin; D016559:Tacrolimus