GRAFT-VERSUS-LEUKEMIA IN RAT MHC-MISMATCHED BONE-MARROW TRANSPLANTATION IS MERELY AN ALLOGENEIC EFFECT

One of the major problems in the treatment of leukemia with bone marro w transplantation (BMT) remains leukemia relapse. It has been clearly shown that graft-versus-host disease (GVHD) is accompanied by a graft- versus-leukemia reaction (GVLR) which reduces the incidence of leukemi a relapse. To date, discussion is still going on as to whether GVHD an d GVLR are either two different reactions or are exerting their effect s through the same mechanism(s). In two rat leukemia models, namely th e Brown Norway acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia L4415, total body irradiation (TBI) was given to induce a state of so-called minimal residual disease (MRD). Subsequent ly, it was attempted to evoke a GVLR distinct from GVHD by using semi- allogeneic hybrid-to-parent or parent-to-hybrid BMT, with or without t he addition of graded numbers of lymphocytes. In both leukemia models applying hybrid-to-parent BMT, the addition of high numbers of semi-al logeneic lymphocytes to the semi-allogeneic graft had no antileukemic effect. In parent-to-hybrid BMT, the grafts sharing their alloantigens with the leukemia cells did not induce an anti-leukemic effect, irres pective of the number of lymphocytes present in the graft or the induc tion of evident GVHD. When the parental graft was histoincompatible wi th the leukemia cells, transplantation of bone marrow alone induced a significant increase in life span correlating with 2.8 log leukemia ce ll kill (LCK). Addition of graded numbers of histoincompatible splenoc ytes to the graft further increased the anti-leukemic effect (maximall y correlating with 4.0 LCK) without signs of obvious GVHD or, with hig her numbers of splenocytes, induced acute lethal GVHD. Thus, the resul ts indicate that the GVLR observed post-MHC mismatched BMT in these ra t leukemia models for ALL and AML are mere allogeneic effects, insepar able from GVHD.