Pharmacodynamics of T-cell function for monitoring immunosuppression.
OBJECTIVE
Recent studies show that measuring pharmacodynamic (PD) effects offers a unique possibility to predict immunosuppression. Thus, in this study we have monitored the PD properties of immunosuppressants on diverse T-cell functions in heart transplant (HTx) recipients.


METHODS
PDs and blood concentrations (PK) of three different basis-immunosuppressive drugs were studied: cyclosporin A (CsA); tacrolimus (TRL) and sirolimus (SRL). T-cell function was analysed by expression of proliferating cell nuclear antigen (PCNA) labelling, expression of cytokines (IL-2, IFN-gamma) and surface antigen (for example, CD25) by FACS analysis.


RESULTS
In group I, at time points C0 and C2, increased CsA-PK significantly inhibited expression of IL-2, IFN-gamma, PCNA and CD25 (P < 0.05). Correlations (r(2)) at C2 between inhibition of T-cell functions (PD) with PK and with drug doses were: CsA-PK: 0.71-0.91 and CsA-dose: 0.73-0.87. In group II, increased TRL-PK over time did not further inhibit expression of CD25, but inhibited PCNA expression more on day 3, and IL-2 and IFN-gamma expression was significantly higher on days 2 and 3 compared to PD effects of CsA (P < 0.05). Blood SRL concentrations in C0 group III, increased on day 1 and remained stable at days 3 and 4. Expression of PCNA was not altered in the SRL-PK category, whereas expression of CD25 was higher and expression of cytokines was lower than PD effects of CsA.


CONCLUSIONS
Our results show that PD effects on T-cell function can be used to monitor immunosuppression bringing potential to increase the efficacy and safety of immunosuppressive therapy after HTx.
Barten
M J
MJ
Department of Cardiac Surgery, Heart Center Leipzip, Leipzig, Germany. bartenm@medizin.uni-leipzig.de
Tarnok
A
A
Garbade
J
J
Bittner
H B
HB
Dhein
S
S
Mohr
F W
FW
Gummert
J F
JF
D000368:Aged; D000954:Antigens, Surface / Q000032:analysis; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D020123:Sirolimus / Q000493:pharmacokinetics / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000494:pharmacology; D013997:Time Factors
D000954:Antigens, Surface; D016207:Cytokines; D007166:Immunosuppressive Agents; D018809:Proliferating Cell Nuclear Antigen; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus