The Effect of Human Il-2-Activated Natural Killer and T Cells on Graft-Versus-Host Disease and Graft-Versus-Leukemia in Scid Mice Bearing Human Leukemic Cells

We have previously reported that xenogeneic lethal acute graft-versus-host disease (GVHD) was induced by transplantation of a mixture of human IL-2 activated natural killer (NK) and T cells into SCID mice conditioned with 4 Gy total-body irradiation (TBI), but not by IL-2-activated pure human T cells or NK cells. TBI and transplantation of the mixture of activated cells were both required to produce the lethal effect. We now report the effect of human IL-2 activated NK, T, or NK+T effector cells on the development of acute and chronic GVHD and GVL in SCID mice bearing human leukemic cells. Ten days after being inoculated i.v. with 2 x 10(7) human U-937 or K-562 leukemic cells, SCID mice, hereafter termed hu-leukemic mice, were radiated with 4 Gy TBI and transplanted i.v. with 5 x 10(7) human IL-2-activated NK, T, or NK+T effector cells. Hu-leukemic control mice received neither TBI nor effector cell transplantation. Acute GVHD-positive control SCID mice were transplanted with 5 x 10(7) H-2-incompatible C57Bl/6 splenocytes following 4 Gy TBI. The mice were observed for signs of GVHD and leukemia for 90 days. Twenty of 20 non-effector cell-transplanted control hu-leukemic mice developed signs related to leukemia and died with leukemic infiltration in the brain, liver, kidney, and lung 50-65 days after inoculation. Flow cytometry (FC) demonstrated 21-89% human leukemic cell infiltration in the bone marrow. Fourteen of 14 hu-leukemic mice transplanted with NK+T effector cells did not develop signs of advanced leukemia but died within 17 days of acute GVHD. FC demonstrated no human leukemic cells in their marrow. Twelve of 15 and 18 of 25 hu-leukemic mice transplanted with either NK or T cells survived 90 days without any evidence of symptomatic leukemia (P < 0.01 compared with non-effector cell-transplanted groups). NK-transplanted hu-leukemic animals experienced mild-to-moderate acute GVHD during the first 10-20 days posttransplantation, but gradually recovered and did not develop chronic GVHD. Hu-leukemic animals transplanted with T effector cells manifested no signs of leukemia or acute GVHD but chronic GVHD skin lesions appeared 80-90 days after transplantation. We conclude that acute GVHD, chronic GVHD, and GVL are associated but separable phenomena.