DELAYED CARDIAC ALLOGRAFT-REJECTION DUE TO COMBINED CYCLOSPORINE AND ANTIOXIDANT THERAPY

The effecters of cell death in allograft rejection are poorly understo od. Oxygen derived free radicals (ODFR) may participate in graft destr uction. We examined the impact of the antioxidants ascorbic acid (AA) and alpha-tocopherol (AT) with low dose CsA on rat cardiac allograft s urvival. Lewis rats that had undergone heterotopic abdominal cardiac t ransplantation with Wistar-Furth allografts (day 0) were divided into 6 groups. Group 1 was the control group; groups 2 and 3 received AA (1 200 mg/kg), and groups 4 and 5 received AT (800 IU/kg) by gavage daily until rejection. Groups 3, 5, and 6 were given CsA (2.5 mg/kg i.m.) d ays 1-15. Allograft rejection times (in days) were 7.7+/-1, 10.3+/-1.5 (P<0.01 vs. group 1), 37.1+/-6.4 (P<0.01 vs. group 1, P=0.0004 vs. gr oup 6), 9.0+/-1.4, 26.5+/-3.6 (P<0.01 vs. group 1, P<0.03 vs. group 6) , and 20+/-4.9 (P<0.01 vs. group 1) for groups 1, 2, 3, 4, 5, and 6. T o assess the impact of AA on ODFR production, chemiluminescence was pe rformed on zymosan-activated Lewis whole blood from control rats and r ats administered AA. AA significantly decreased peak chemiluminescence (P<0.05) as compared with nontreated rats indicating effective ODFR s cavenging. To determine whether AA and AT inhibit lymphocyte stimulati on, mixed lymphocyte response testing was performed with irradiated Wi star-Furth lymphocytes as stimulator cells for Lew responder cells fro m rats treated as groups 3, 5, and 6. CsA significantly suppressed (P< .05) proliferation as compared with untreated controls. Neither AA nor AT enhance CsA's immunosuppressive effect by mixed lymphocyte respons e testing. In summary, prolongation of allograft survival with antioxi dants AA and AT does not result from abrogation of lymphocyte responsi veness or alteration in CsA bioavailability. Rather, these data sugges t that ODFR are involved in allograft destruction and support a role f or effective antioxidant therapy in the treatment of allograft rejecti on.