The effect of combination therapy with EPC-K1 and low-dose cyclosporine to pulmonary allograft after rat lung transplantation.
BACKGROUND
EPC-K1, a diester of alpha-tocopherol and ascorbic acid, has a hydroxyl radical scavenging effect and also has antiinflammatory properties through its phospholipase A2 inhibitory effect. With a view to decreasing the total dose of cyclosporine, the effect of a combination of EPC-K1 and cyclosporine on rejection was investigated by use of a rat orthotopic left lung transplantation model.


METHODS
Orthotopic left lung transplantation was performed with brown Norway rats as donors and Lewis rats as recipients. Recipients were assigned to one of four experimental groups. Control group animals were given no immunosuppression. The EPC-K1 group received continuous intraperitoneal infusion of EPC-K1 (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-K1 + cyclosporine group received both EPC-K1 and cyclosporine in the same manner as the EPC-K1 and cyclosporine groups. Recipients were killed on POD 7, and the transplanted lungs were examined histologically and graded in a blinded fashion (grade 0 to 4). The effect of EPC-K1 and cyclosporine treatment on the primary immune response was examined by mixed lymphocyte reaction (MLR) between brown Norway rat stimulator cells (treated with mitomycin) added to Lewis rat responder lymphocytes.


RESULTS
Control group animals exhibited the severe destructive changes of grade 4 lung rejection. The EPC-K1 + cyclosporine group showed significantly less graft rejection compared with the EPC-K1 group and the cyclosporine group (p < 0.01). In MLR assay, the EPC-K1 + cyclosporine group (793 +/- 210 cpm) showed significantly suppressed lymphocyte proliferation compared with the control group (2188 +/- 360 cpm), EPC-K1 group (1869 +/- 541 cpm), and cyclosporine group (1873 +/- 326 cpm) (p < 0.01).


CONCLUSIONS
EPC-K1 significantly improves effects of cyclosporine at lower doses both in preventing pulmonary allograft rejection and in suppressing lymphocyte proliferation in MLR.
Udaka
T
T
Department of Surgery II, Okayama University Medical School, Japan.
Misao
T
T
Aoe
M
M
Date
H
H
Andou
A
A
Shimizu
N
N
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D016166:Free Radical Scavengers; D007166:Immunosuppressive Agents; D014810:Vitamin E; C066638:potassium ascorbyl tocopheryl phosphate; D016572:Cyclosporine; D010741:Phospholipases A; D054467:Phospholipases A2; D001205:Ascorbic Acid