Cyclosporine abrogation of second-set rejection: dependence upon major histocompatibility complex disparity

The purpose of these experiments was to evaluate the use of cyclosporine (CyS) in preventing accelerated rejection in donor-specific presensitized hosts by comparing its efficacy in donor-recipient strain combinations that were either haploidentical or completely mismatched at the major histocompatibility complex (MHC). Lewis X Brown Norway F1 (LBN) (Rt1(1)n) secondary heart allograft survival was prolonged indefinitely in CyS-treated Lewis (Rt1(1] recipients while ACI (Rt1a) grafts were ultimately rejected despite maintenance use of CyS. However, graft survival was significantly prolonged in these latter experiments with mean survival times (MSTs) of 29.4 +/- 32.1 days (CyS 10 mg/kg/day) and 19.4 +/- 21.1 days (CyS 15 mg/kg/day) compared to both untreated second-set controls (MST of 3.9 +/- 0.8 days, P less than 0.05), and untreated primary graft recipients (MST of 6.9 +/- 0.4 days, P less than 0.05). An attempt to identify suppressor cells in the long-term Lewis recipients of LBN hearts using an adoptive transfer experiment was unsuccessful when the spleen donors were still receiving CyS. Conversely, in a control experiment using spleens from CyS prolonged primary graft recipients in which splenectomy was performed after cessation of CyS, subsequent adoptive transfer did significantly prolong test heart graft survival in three of seven rats suggesting that suppressor cells may have been present. These data suggest that CyS is an effective immunosuppressant in presensitized hosts when MHC disparity is incomplete but that it cannot indefinitely prevent rejection in donor-recipient combinations that are completely mismatched at the MHC. Moreover, they suggest that splenic suppressor cells may not be present in animals concurrently receiving CyS.