Correlation between enhancement of graft-versus-leukemia effects followingallogeneic bone marrow transplantation by rIL-2 and increased frequency ofcytotoxic T-lymphocyte precursors in murine myeloid leukemia

A model of mouse acute myeloid leukemia (mAML) was used to study the effect or mechanism mediating the graf-tversus-leukemia (GVL) effects in recipient s of allogeneic bone marrow cells (BMC). mAML-bearing SJL/J (H-2(s)) mice w ere lethally irradiated and then transplanted with a mixture of BMC and spl een cells (SC) derived from normal syngeneic or allogeneic mice. To augment the GVL effect, recipients were injected intraperitoneally with recombinan t human interleukin-2 (rIL-2) (1.2 x 10(5) IU) for 3 consecutive days, star ting one day post BMC + SC transplantation. Spleen cells from treated recip ients were adoptively transferred to untreated secondary SJL/J mice to test for the existence of residual tumor cells. All the secondary recipients of SC from mAML-bearing SJL/J mice rescued with syngeneic (SJL/J) or allogene ic (B10.S) BMC+SC (H-2(s)) differing at minor antigens of the histocompatib ility complex (MiHC) developed leukemia and died. In sharp contrast, none o f the secondary recipients of SC obtained from identical mAML-bearing mice rescued with B10.S BMC + SC but activated in vivo with IL-2 developed leuke mia. Adoptive recipients of SC obtained from mAML-bearing recipients of maj or histocompatibility complex (MHC)-disparate (C57BL/6, H-2(b)) cells remai ned free of leukemia regardless of the use of rIL-2. In parallel with the i n vivo findings, a 4-day in vitro exposure of splenocytes to 6 x 10(3) IU/m l rIL-2 resulted in a 5- to 20-fold increase in the frequency of alloreacti ve cytotoxic T-lymphocyte (CTL) precursors (CTLp) across MiHC and MHC barri ers and a 2- to 6-fold increase in their cytotoxic activity. Our data sugge st that augmentation of GVL effects by rIL-2 may be due to CTL activation b y rIL-2, not excluding the potential beneficial role of rIL-2-activated all ogeneic natural killer cells and MHC non-restricted killer cells. Cumulativ ely, our results suggest potentially beneficial effects of rIL-2, when used jointly with bone marrow transplantation or allogeneic cell therapy, on er adication of leukemia.