ABROGATION OF GRAFT-VS.-LEUKEMIA ACTIVITY AFTER DEPLETION OF CD3(-CELLS IN A MURINE MODEL OF MHC-MATCHED PERIPHERAL-BLOOD PROGENITOR-CELL TRANSPLANTATION (PBPCT)() T)

Using a murine transplantation model, we simulated a clinical situatio n in which major histocompatibility complex (MHC)-identical allogeneic peripheral blood progenitor cells (PBPCs) are transplanted for the tr eatment of a malignant disease that is resistant to resting natural ki ller (NK) cells but sensitive to cytokine-activated NK cells and T cel l-mediated antitumor activity. We determined the influence of selectiv e T cell depletion of allogeneic PBPC grafts on graft-vs.-leukemia (GV L) activity and investigated the effectiveness of ex vivo treatment wi th NK cell-activating cytokines to compensate for the putative loss of T cell-derived factors stimulating natural cytotoxicity. After pretre atment of Balb/c (H-2(d)) recipients with 7.5 Gy of total body irradia tion, 2x10(7) rhG-CSF-mobilized PBPCs of splenectomized syngeneic or M HC-identical DBA (H-2(d)) mice were transferred. Selective T cell depl etion (TCD) was performed by immunomagnetic purging with a mononoclona l antibody directed against CD3. In some experimental groups, T cell-d epleted PBPCs were incubated with 200 U/mL interleukin (IL)-2 and 100 U/mL IL-12 for 24 hours. To investigate antileukemic activity in vivo, recipient mice were inoculated with 1x10(5) A20 cells (a B-lymphoblas tic leukemia of Balb/c origin) 2 days before PBPC transplantation (PBP CT). After transplantation of unmanipulated allogeneic cells, 25% of t he animals died with signs of graft-vs.-host disease (GVHD) but 71% we re free from relapse 100 days after PBPCT. After TCD of allogeneic gra fts with anti-CD3, the incidence of GVH-related mortality was below 5% but the leukemia-free survival rate was significantly (p < 0.05) decr eased to 25% and thus was similar to that observed after syngeneic PBP CT (17%). When CD3-depleted grafts were incubated with IL-2 and IL-12, 45% of the animals remained free from leukemia; however, the differen ce was not statistically significant. Our results suggest that ex vivo activation of residual NK cells with IL-2 and IL-12 does not fully co mpensate for the abrogation of GVL activity after depletion of CD3(+) T cells from MHC-matched PBPCT.