Enhancement of the immunosuppressive effect of cyclosporin A by ciprofloxacin in a rat cardiac allograft transplantation model

Abstract

Abstract Ciprofloxacin hyperinduces interleukin-2 production in stimulated human and mouse lymphocytes. In this study, an enhanced and prolonged interleukin-2 response was also detected in polyclonally stimulated rat splenocytes in the presence of ciprofloxacin (5–80 μ/ml) compared to control cells without any antibiotic. Ciprofloxacin was able to counteract the immunosuppressive effect of 10 ng/ml cyclosporin A (CyA) but did not interfere with higher CyA concentrations. In parallel, ciprofloxacin did not influence thymidine uptake in mixed lymphocyte reactions in the presence of CyA. To obtain an in vivo application of these findings, graft survival was studied by performing rat cardiac allograft transplantations in the presence or absence of CyA. Brown Norway rats served as donors and Wistar Furth rats as recipients. Ciprofloxacin was injected intraperitoneally either at a high-dose regimen (240 mg/kg per 24 h) into rats every 8th h starting 1 day before transplantation until day 21 or graft loss, or it was injected at a low and clinically relevant dose regimen (45 mg/kg per 24 h) until day 9. CyA was administered orally (10 mg/kg per 24 h) from day 1 through day 9. Ciprofloxacin given alone at a high-dose regimen resulted in a median graft survival of 14.8 days, which was significantly longer than graft survival in rats without treatment (median 8.0 days). A low-dose regimen of ciprofloxacin alone did not affect graft survival. Ciprofloxacin at a highdose regimen combined with CyA prolonged graft survival to a median of 24.0 days compared to 20.5 days with CyA alone. Ciprofloxacin administered in the drinking water (200 mg/kg per 24 h) until day 9 in addition to CyA did not affect graft survival. However, when the same dose regimen was used in experiments with PVG rats as donors and Wistar/Kyoto as recipients, graft survival was significantly prolonged to a median of 45 days. Ciprofloxacin, given orally without the addition of CyA, did not influence graft survival in either of the two strain combinations. Thus, our data show that ciprofloxacin has no negative impact on heart graft survival rats. It remains to be clarified whether ciprofloxacin influences graft survival in humans.