INTERLEUKIN-12 PRESERVES THE GRAFT-VERSUS-LEUKEMIA EFFECT OF ALLOGENEIC CD8 T-CELLS WHILE INHIBITING CD4-DEPENDENT GRAFT-VERSUS-HOST DISEASE IN MICE

We have recently demonstrated that a single injection of 4,900 IU of i nterleukin-12 (IL-12) on the day of bone marrow transplantation (BMT) markedly inhibits acute graft-versus-host disease (GVHD) in a fully ma jor histocompatibility complex plus minor antigen-mismatched BMT model (A/J --> B10, H-2(a) --> H-2(b)), in which donor CD4(+) T cells are r equired for the induction of acute GVHD, We show here that donor CD8-d ependent graft-versus-leukemia (GVL) effects against EL4 (H-2(b)) leuk emia/lymphoma can be preserved while GVHD is inhibited by IL-12 in thi s model. In mice in which IL-12 mediated a significant protective effe ct against GVHD, marked GVL effects of allogeneic T cells against EL4 were observed. GVL effects against EL4 depended on CD8-mediated allore activity, protection was not observed in recipients of either syngenei c (B10) or CD8-depleted allogeneic spleen cells. Furthermore, we analy zed IL-12-treated recipients of EL4 and A/J spleen cells which survive d for more than 100 days, No EL4 cells were detected in these mice by flow cytometry, tissue culture, adoptive transfer, necropsies, or hist ologic examination. Both GVL effects and the inhibitory effect of IL-1 2 on GVHD were diminished by neutralizing anti-interferon-gamma (IFN-g amma) monoclonal antibody. This study demonstrates that IL-12-induced IFN-gamma production plays a role in the protective effect of IL-12 ag ainst GVHD. Furthermore, IFN-gamma is involved in the GVL effect again st EL4 leukemia, demonstrating that protection from CD4-mediated GVHD and CD8-dependent anti-leukemic activity can be provided by a single c ytokine, IFN-gamma. These observations may provide the basis for a new approach to inhibiting GVHD while preserving GVL effects of alloreact ivity. (C) 1997 by The American Society of Hematology.