Gee, I.; Trull, A.; Charman, S.; Alexander, G.J.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA58
Academic Journal
Introduction: Sirolimus is an immunosuppressive drug that is being used increasingly in transplant recipients. It has been observed that some patients develop bacterial sepsis during treatment. Methods: We have developed a physiological in vitro model to investigate the effects of therapeutic concentrations of sirolimus on the neutrophil oxidative burst (NOB), a mechanism by which immunity to bacterial and fungal infection may be impaired. Whole blood from 24 healthy subjects was equilibrated with 0, 1, 5, 10 and 50µg/L sirolimus or 60mg/L propofol (a known inhibitor of neutrophil function) for 2 hours at 37°C. The cells were washed and the neutrophils stimulated with phorbol myristate acetate (PMA). NOB was measured by flow cytometry using the fluorescent marker dichlorofluorescein. Results: A significant mean inhibition of NOB (95 % C.I. of mean % inhibition did not overlap zero) was found with 50mg/L sirolimus (mean 6.3; C.I. 1.5, 11.1%) and 60mg/L propofol (mean 5.1; C.I. 0.4, 9.8 %). 10mg/L sirolimus also inhibited N.O.B. (mean 4.6; C.I. -1.3, 10.6; NS) but inhibition was <1.5% at lower concentrations. Repeated measures ANOVA confirmed a linear relationship between sirolimus concentrations and inhibition of NOB (P=0.01). The two hour incubation period had no effect on red blood cell integrity or white cell viability in vitro. Conclusion: Sirolimus had a dose-dependent inhibitory effect on NOB but this was not significant at Iow therapeutic concentrations. This may partly explain the predisposition to sepsis in patients receiving sirolimus.


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