Hyporesponsiveness in alloreactive T-cells by NF-kappaB inhibitor-treated dendritic cells: resistance to calcineurin inhibition.
Dendritic cells (DC) are the most potent antigen-presenting cells (APC) initiating primary T-cell responses. Beyond this immunostimulatory function, certain DC subsets have been shown to induce T-cell tolerance in vitro and in vivo. In this study, immature monocyte-derived DC were activated in the presence of the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) and characterized with regard to phenotype, cytokine production and allostimulatory potential. Furthermore, the functional consequences of calcineurin inhibition were studied in T cells exposed to PDTC-modulated DC. We demonstrate that PDTC treatment of DC leads to an arrest in maturation as reflected by down-regulated major histocompatibility complex (MHC) antigens and costimulatory molecules, suppressed immunostimulatory cytokines and an impaired capability to support allogeneic T-cell activation. Allogeneic T cells challenged with PDTC-treated DC are refractory upon restimulation with alloantigens but not to polyclonal stimuli. Interestingly, the successful establishment of alloantigenic hyporesponsiveness is not prevented by concomitant calcineurin inhibition in vitro as well as in T cells from patients under cyclosporine A (CsA)-based immunosuppression ex vivo. These data may have important implications for the design of clinical regimens for the establishment of antidonor hyporeactivity in organ transplantation using in vitro-modulated DC.
Institute of Immunology, University of Vienna Medical School, Borschkegasse 8a, A-1090 Vienna, Austria.
Marcus D
MD
Säemann
Peter
P
Kelemen
Georg A
GA
Böhmig
Walter H
WH
Hörl
Gerhard J
GJ
Zlabinger
D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000097:blood; D000975:Antioxidants / Q000494:pharmacology; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D006684:HLA-DR Antigens; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013859:Thiocarbamates / Q000494:pharmacology
D015703:Antigens, CD; D000975:Antioxidants; D016207:Cytokines; D006684:HLA-DR Antigens; D016328:NF-kappa B; D013859:Thiocarbamates; C066229:prolinedithiocarbamate; D011392:Proline