Combination of immunosuppressive drugs leaves specific "fingerprint" on gene expression in vitro.
Following organ transplantation many patients suffer from drug-related side effects, or receive more immunosuppression than necessary to prevent rejection. Hence, parameters are needed to tailor the immunosuppressive therapy to the individual needs of an organ recipient. The aim of this study was to determine whether drug combinations provoke specific gene expression patterns in a simple assay system in vitro. Stimulated peripheral blood lymphocytes were cultured in the presence of cyclosporine A, tacrolimus, mycophenolic acid, everolimus and sirolimus, or combinations thereof. Using a cDNA microarray, we found that all samples clustered in drug-specific groups. Gene expression profiles were almost identical in PBL treated with either cyclosporine A or tacrolimus, and with either sirolimus or everolimus. More than 50 genes were synergistically affected by combinations of calcineurin-inhibitors and TOR-inhibitors and drug-specific regulated genes could be identified for both substance groups. Our data suggest that in vitro gene profiling can be used to describe synergistic effects of immunosuppressive drugs. Furthermore, our approach may help to identify marker genes urgently needed to optimize and individualize immunosuppressive drug regimens after organ transplantation.
Rumberger
Brigitta
B
Renal Division, Department of Internal Medicine, University Hospital, Freiburg, Germany. brigitta.rumberger@krupp-krankenhaus.de
Kreutz
Clemens
C
Nickel
Christian
C
Klein
Marinella
M
Lagoutte
Severine
S
Teschner
Sven
S
Timmer
Jens
J
Gerke
Peter
P
Walz
Gerd
G
Donauer
Johannes
J
D000328:Adult; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D000068338:Everolimus; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D009173:Mycophenolic Acid / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus