INDUCTION OF DONOR-SPECIFIC UNRESPONSIVENESS TO RAT CARDIAC ALLOGRAFT BY DONOR LEUKOCYTES AND CYCLOSPORINE

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Abstract
Many recent reports have emphasized the importance of donor antigens in the induction of allograft tolerance. This study examines the effect of pretransplant infusion of 108 donor leukocytes (DL) combined with peritransplant cyclosporine (CsA) on W/F cardiac allograft survival in Lewis rats. Peritransplant recipient treatment consisted of CsA 20 mg/kg given i.m. on days 0, +1, and +2 relative to heart transplantation. Lewis recipients, 5-8 per group, were pretreated with 108 DL with or without peritransplant CsA. A single DL transfusion on day -3 or day -7 prior to transplantation significantly prolonged the mean survival time (MST) of W/F hearts from 7.0 .+-. 0.9 days in controls to 12.2 .+-. 4.5 days and 12.4 .+-. 1.0 days (P < 0.01), respectively. Two DL infusions on days -7 and -3 or on days -14 and -7 prolonged the MST to 10.6 .+-. 1.3 days (P < 0.02) and 16.4 .+-. 2.8 days (P < 0.001), respectively. The administration of peritransplant CsA alone significantly prolonged W/F heart allograft survival to 43.1 .+-. 2.7 days. When pretransplant DL transfusion on day -3 was combined with CsA treatment, 4/8 animals maintained their grafts indefinitely (> 100 days). Similarly, DL infusion on day -7 with peritransplant CsA led to indefinite graft survival in 3/5 animals. Administration of DL on days -7 and -3 combined with CsA resulted in indefinite graft survival (> 100 days) in 4/6 animals. Transfusion of DL on day -3 alone or in combination with peritransplant CsA, had no effect on a third-party (ACI) heart allograft survival prolongation compared with appropriate controls. To define the underlying mechanisms responsible for donor-specific unresponsiveness in this model, pooled sera and unseparated spleen cells were passively transferred from recipients of long-term cardiac allografts to syngeneic rats receiving donor-type (W/F) or third-party (ACI) cardiac allografts. Transfer of serum (1 ml on days 0, and 1, 0.5 ml on days +2, +3, and +4) from ungrafted recipients of DL on days -14 and -7 led to significant donor graft survival of 9.8 .+-. 0.4 days (P < 0.02) in unmodified hosts. Similarly, passive transfer of serum obtained at 20 and 100 days after transplantation significantly prolonged the MST of donor-type hearts in syngeneic untreated hosts to 11.3 .+-. 0.8 and 10.0 .+-. 1.1 days, respectively. Passive transfer of 1 .times. 108 spleen cells obtained at 20 and 100 days after transplantation from recipients of long-term cardiac allografts prolonged the donor test grafts in naive hosts to 13.5 .+-. 2.6 and 10.8 .+-. 1.9 days, respectively. Transfer of both sera and spleen cells obtained at 20 days after transplantation had no effect on a third-party (ACI) heart allograft survival. These results suggest that pretransplant DL infusion combined with a brief peritransplant CsA can induce immunologic unresponsiveness that is dependent on collaboration between serum-specific suppressor factor or antibody, and the generation of donor-specific suppressor cells. This study reemphasizes the importance of leukocytes in immunologic manipulation using donor-specific transfusions and describes the strong synergistic effect of CsA on the use of DL.