Individual variability in cyclosporin A sensitivity: the assessment of functional measures on CD28-mediated costimulation of human whole blood T lymphocytes.
The quantitative analysis of cyclosporin A (CsA) effects might be helpful for optimizing immunosuppressive treatment after allogeneic organ transplantation in individual patients, as rejection can occur despite the existence of CsA blood levels within therapeutic ranges. Previous investigations found that costimulation of the CD28 pathway generally mediates CsA-resistant proliferation of T cell receptor (TCR)-activated T lymphocytes. However, here we describe considerable interindividual variation regarding the immunosuppressive effects of CsA (1000 microg/L) on anti-CD3/CD28 T cell costimulation in a human whole blood assay. In the in vitro study, we found a significant reduction of T cell proliferation, activation marker expression (CD25, CD69) on the T cell surface, and interleukin-2 (IL-2) protein expression in whole blood samples of all healthy subjects (n = 11). However, the investigation of cytokine mRNA profiles revealed variable results of in vitro CsA sensitivity. Whole blood samples of 3 of 11 healthy individuals demonstrated a marked suppression of IL-2 mRNA expression (>50%) and a partial inhibition of IL-4, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) mRNA expression on addition of CsA. In contrast, the remaining 8 healthy individuals had cytokine mRNA expression levels that were unaffected or even increased when CsA was administered in vitro. In patients undergoing CsA monotherapy (ex vivo study, n = 9), we found a significant suppression of IL-2 mRNA levels in 4 of 9 patients ex vivo. Thus, we cannot confirm a universal CsA resistance of T cells on anti-CD3/CD28 costimulation. Instead, our results suggest an individual degree of CsA sensitivity that might be more consistent with clinical experience. Prospective studies are necessary to determine if individual degrees of CsA sensitivity correlate with clinical events and are associated with a low or high risk of transplant rejection.
Institute of Immunology and Transfusion Medicine, University of Lübeck Medical School, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Christoph
C
Härtel
Hans-Jörg
HJ
Hammers
Peter
P
Schlenke
Lutz
L
Fricke
Nina
N
Schumacher
Holger
H
Kirchner
Michael
M
Müller-Steinhardt
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers; D001773:Blood Cells / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics; D016030:Kidney Transplantation; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects; D000099192:CD69 Antigens
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015415:Biomarkers; D018106:CD28 Antigens; D016572:Cyclosporine; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D007376:Interleukin-2; D015847:Interleukin-4; D037181:Lectins, C-Type; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens