Graft survival in a rhesus renal transplant model after immunotoxin-mediated T-cell depletion is enhanced by mycophenolate and steroids

Background. Anti-CD3 immunotoxin (IT), a T-cell-depleting agent, prolongs s urvival of renal allografts in a rhesus monkey model without the need for l ongterm immunosuppression. In this study we sought to further prolong allog raft survival by giving short-term conventional immunosuppression. simultan eous with IT administration. Methods. MHC class II mismatched, juvenile rhesus monkeys were paired as do nor and recipient for renal transplantation. Recipients received two to thr ee daily doses of IT starting on the day of transplantation. Additional imm unosuppression was given for no more than 60 days. Graft function was monit ored by serum creatinine and renal biopsies. Flow cytometry was used to mon itor T-cell recovery. Results. Graft survival time (GST) in animals receiving IT was prolonged co mpared with controls with 50% of IT-treated monkeys surviving > 100 days. A nimals treated with IT plus mycophenolate mofetil (MMF) and steroids had si gnificantly enhanced GST (mean GST, 305 days) compared with those treated w ith IT alone (mean GST, 94 days). In contrast, addition of cyclosporine or 40-O-[2-Hydroxyethyl]rapamycin did not significantly increase graft surviva l time. A comparison among animals from all treatment groups with short (< 100 days) and long (> 100 days) GST demonstrated that those with the shorte r GST had a higher blood T-cell count 2 weeks after transplantation. Full r ecovery of CD4(+) T cells required longer than 6 months. Conclusions. A combination with MMF and steroids given for 4 days after ren al allograft transplantation significantly increases GST in IT-treated monk eys. We hypothesize that MMF and steroids suppress the initial T-cell activ ation mediated by IT.