Greater Efficacy of Tolerance Induction with Cyclosporine versus Tacrolimus in Composite Tissue Allotransplants with Less Myeloablative Conditioning

Abstract

Previous studies demonstrated that both cyclosporine and tacrolimus in combination with antilymphocyte globulin could facilitate mixed chimerism and induce tolerance to composite tissue allotransplants under partial myeloablative conditioning. The purpose of this study was to compare the efficacy of cyclosporine and tacrolimus. Brown-Norway and Lewis rats were used as composite tissue allotransplant donors and recipients, respectively. Cyclosporine groups I (n = 6), II (n = 9), and III (n = 5) received subcutaneous injection of 16 mg/kg cyclosporine (days 0 to 10); intraperitoneal injection of 5 mg of antilymphocyte globulin (days -1 and 10); and 0-, 200-, and 400-cGy total body irradiation (day -1), respectively. Tacrolimus groups IV (n = 6), V (n = 7), and VI (n = 8) received intraperitoneal injection of 1 mg/kg tacrolimus (days 0 to 10) and 5 mg of antilymphocyte globulin (days -1 and 10); and 0-, 200-, and 400-cGy total body irradiation (day -1), respectively. Recipients underwent hind-limb osteomyocutaneous flap composite tissue allotransplantation on day 0. Chimerism levels were determined 2 weeks after composite tissue allotransplantation, and acceptance was defined as complete survival of the composite tissue allotransplant to the endpoint of the experiment at 150 days. Chimerism levels 2 weeks after composite tissue allotransplant averaged 3.4, 4.9, 29, 2.4, 4.9, and 16 percent composite tissue allotransplant, and acceptance rates were 0, 33.3, 80, 0, 0, and 13 percent in group I, II, III, IV, V, and VI, respectively. Despite relatively late development for clinical use in transplantation, tacrolimus has not proved advantageous for composite tissue allotransplant acceptance and tolerance when compared with cyclosporine.