Cytokines and cell surface receptors as target end points of immunosuppression with cyclosporine A.
Targets of cyclosporine (CsA) were identified from an array of stimulated lymphocyte responses (sLR) comprising 34 stimulation conditions in whole blood from 3 normal human volunteers (NHV) containing clinically relevant CsA concentrations (0-1200 ng/ml) in vitro. In whole blood from 5 additional NHV, selected targets (intracellular interleukin-2 [IL-2], tumor-necrosis factor-alpha [TNF-alpha], and interferon-gamma [IFN-gamma]) were measured in phorbol myristate acetate (PMA)-ionomycin-stimulated T lymphocytes. Effect:concentration relationships were analyzed with E(max) pharmacodynamic (PD) equations and expressed as the concentration associated with one-half maximal inhibitory effect (EC(50)). CsA demonstrated a rich matrix of inhibitory effects on T cells (CD3(+)), B cells (CD19(+)), dendritic cells (DC) (CD11c(+)), and basophils (CD123(+)) but not on monocytes (CD14(+)) (n = 3). PD analyses suggested that the EC(50) of CsA (1) for IL-2 in CD3(+) cells in NHV (n = 8) was similar to the EC(50) demonstrated by us previously in CD4(+) cells from transplanted patients (n = 13) (EC(50) = 260 ng/ml vs. 249 ng/ml), (2) for each cytokine was different under identical stimulation conditions (TNF-alpha, 324 ng/ml; IFN-gamma, 504 ng/ml), and (3) was relatively constant for a given cytokine under different stimulation conditions (e.g., PMA-ionomycin or the staphylococcal enterotoxin B [SEB] superantigen). In conclusion, inhibition of cytokine targets by CsA is concentration dependent. Further, a given CsA concentration may produce similar inhibitory effects across different stimulation conditions. Measurement of cytokine target expression may, therefore, allow effect-controlled administration of CsA during clinical transplantation.
Sindhi
R
R
Children's Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. sindhir@chplink.chp.edu
Allaert
J
J
Gladding
D
D
Koppelman
B
B
Dunne
J F
JF
D000328:Adult; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001491:Basophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000032:analysis*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000944:Antigens, Differentiation, B-Lymphocyte; D015415:Biomarkers; D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine