ENHANCEMENT OF THE IMMUNOSUPPRESSIVE EFFECT OF CYCLOSPORINE-A BY CIPROFLOXACIN IN A RAT CARDIAC ALLOGRAFT TRANSPLANTATION MODEL

Ciprofloxacin hyperinduces interleukin-2 production in stimulated huma n and mouse lymphocytes. In this study, an enhanced and prolonged inte rleukin-2 response was also detected in polyclonally stimulated rat sp lenocytes in the presence of ciprofloxacin (5-80 mu g/ml) compared to control cells without any antibiotic. Ciprofloxacin was able to counte ract the immunosuppressive effect of 10 ng/ml cyclosporin A (CyA) but did not interfere with higher CyA concentrations. In parallel, ciprofl oxacin did not influence thymidine uptake in mixed lymphocyte reaction s in the presence of CyA. To obtain an in vivo application of these fi ndings, 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 w as 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 clinicall y relevant dose regimen (45 mg/kg per 24 h) until day 9. CyA was admin istered orally (10 mg/kg per 24 h) from day 1 through day 9. Ciproflox acin given alone at a high-dose regimen resulted in a median graft sur vival of 14.8 days, which was significantly longer than graft survival in rats without treatment (median 8.0 days). A low-dose regimen of ci profloxacin alone did not affect graft survival. Ciprofloxacin at a hi gh-dose regimen combined with CyA prolonged graft survival to a median of 24.0 days compared to 20.5 days with CyA alone. Ciprofloxacin admi nistered in the drinking water (200 mg/kg per 24 h) until day 9 in add ition to CyA did not affect graft survival. However, when the same dos e regimen was used in experiments with PVG rats as donors and Wistar/K yoto as recipients, graft survival was significantly prolonged to a me dian of 45 days. Ciprofloxacin, given orally without the addition of C yA, did not influence graft survival in either of the two strain combi nations. Thus, our data show that ciprofloxacin has no negative impact on heart graft survival rats. It remains to be clarified whether cipr ofloxacin influences graft survival in humans.