Immunological studies of transplantation tolerance in irradiated rats repopulated with syngeneic hemopoietic cells.

Adult Lewis (LEW) rats that are lethally irradiated, grafted with allogeneic Wistar Furth (WF) hearts and repopulated with syngeneic bone marrow (LEW) become specifically and permanently tolerant to the allografts. In vivo transfer of spleen cells from tolerant animals to sublethally irradiated LEW rats was capable of preventing the rejection of WF cardiac allografts in 16 of 25 animals, suggesting the possibility of suppressor cells. For further characterization of this putative suppressor cell, mixed lymphocyte reactions (MLR) and cell mediated lympholysis (CML) assays were performed with spleen cells from tolerant and normal LEW rats. In 24 of 52 cases, spleen cells from rats bearing intact WF grafts proliferated in response to the tolerated WF alloantigens, and in 27 of 49 cases they were unable to generate effector cells against WF targets, which indicates that many of these animals were competent to respond to donor antigens as represented in bulk MLR. No suppression was found when spleen cells from nonresponsive recipients were mixed with normal LEW spleen cells in vitro either at the sensitization (MLR) or at the effector (CML) phase of the assay. Neither was there consistent in vitro suppression at the sensitization or effector level, with serum from LEW rats bearing long-term WF cardiac allografts. We suggest that the unresponsiveness observed in vivo is mediated by suppressor cells that interfere with the generation of mature effector cells from immature precursors. It is conceivable that suppressor cells that are present in vivo cannot act on mature effector cells generated in vitro. Additionally, or alternatively, the failure to detect suppression in vitro may result from the presence of stimulator cells in vitro that are not representative of stimulator cells seen by the tolerant animals in vivo.