THE EFFECT OF COMBINATION THERAPY WITH EPC-K-1 AND LOW-DOSE CYCLOSPORINE TO PULMONARY ALLOGRAFT AFTER RAT LUNG TRANSPLANTATION

Background: EPC-K-1, a diester of alpha-tocopherol and ascorbic acid, has a hydroxyl radical scavenging effect and also has antiinflammatory properties through its phospholipase A(2) inhibitory effect. With a v iew to decreasing the total dose of cyclosporine, the effect of a comb ination of EPC-K-1 and cyclosporine on rejection was investigated by u se of a rat orthotopic left lung transplantation model. Methods: Ortho topic left lung transplantation was performed with brown Norway rats a s donors and Lewis rats as recipients. Recipients were assigned to one of four experimental groups. Control group animals were given no immu nosuppression. The EPC-K-1 group received continuous intraperitoneal i nfusion of EPC-K-1 (5 mg/kg/day) by osmotic pump on postoperative days (POD) 0 through 6. The cyclosporine group received cyclosporine (1.25 mg/kg/day) intramuscularly on POD 1 through 6. The EPC-K-1, K-1 + cyc losporine group received both EPC-K-1 and cyclosporine in the same man ner as the EPC-K-1 and cyclosporine groups. Recipients were killed on POD 7, and the transplanted lungs were examined histologically and gra ded in a blinded fashion (grade 0 to 4). The effect of EPC-K-1 and cyc losporine treatment on the primary immune response was examined by mix ed lymphocyte reaction (MLR) between brown Norway rat stimulator cells (treated with mitomycin) added to Lewis rat responder lymphocytes, Re sults: Control group animals exhibited the severe destructive changes of grade 4 lung rejection. The EPC-K-1 + cyclosporine group showed sig nificantly less graft rejection compared with the EPC-K-1 group and th e cyclosporine group (p < 0.01). In MLR assay, the EPC-K-1 + cyclospor ine group (793 +/- 210 cpm) showed significantly suppressed lymphocyte proliferation compared with the control group (2188 +/- 360 cpm), EPC -K-1 group (1869 +/- 541 cpm), and cyclosporine group (1873 +/- 326 cp m) (p < 0.01). Conclusion: EPC-K-1 significantly improves effects of c yclosporine at lower doses both in preventing pulmonary allograft reje ction and in suppressing lymphocyte proliferation in MLR.