The pharmacodynamic effect of sirolimus: Individual variation of cytokine mRNA expression profiles in human whole blood samples

Abstract Sirolimus (SRL) has become an important alternative to calcineurin inhibitors due to its unique mechanism of action. Since rejection and poor graft outcome are still frequent problems despite therapeutic-range blood concentrations, pharmacodynamic measurements of its immunosuppressive effects would be of great clinical value to optimize treatment in individual patients. We performed a human whole blood assay using real time cytokine RT-PCR for the pharmacodynamic assessment of SRL. IL-2, IL-4 and IL-6 mRNA levels were quantitatively determined upon T-cell-specific stimulation in healthy individuals ( n =11; in vitro ) and in kidney-transplant patients ( n =3; ex vivo ). Furthermore, IL-2 protein secretion and T-cell proliferation was measured. After 24 h incubation we observed a stronger suppression of IL-2 and IL-4 mRNA expression upon SRL addition ( p p p p in vitro and ex vivo effects. We describe an individual degree of SRL-sensitivity that may correlate with clinical efficacy. Rather than analysis of one single peak, we suggest determination of two absolute cytokine mRNA peak levels for the pharmacodynamic assessment of SRL. However, prospective clinical studies are necessary to determine whether individual degrees of SRL-sensitivity correlate with clinical outcome.