title: Graft-versus-leukaemia activity can be predicted by natural cytotoxicity against leukaemia cells.
abstract: We have investigated graft-versus-leukaemia (GVL) effects after allogeneic bone marrow transplantation (BMT), using three murine leukaemia models, A20 (B lymphocytic), WEHI-3 (myelomonocytic) and PU5-1R (myeloid). Injection of leukaemia cells in a high number (10(6) cells) into syngeneic Balb/c mice (H-2d) invariably led to death with a median survival time of 22 d (A20), 18 d (WEHI-3) and 45 d (PU5-1R). A lower tumour load of A20 (5 x 10(5) cells) was used in some experiments resulting in a leukaemic death rate of 94%. Lethal total-body irradiation followed by syngeneic BMT prolonged survival (P<0.05) for animals bearing the leukaemia A20 and WEHI-3 but was unsuccessful for animals injected with cells from the monocytic leukaemia PU5-1R. Graft-versus-host (GVH)-nonreactive marrow of (C57 x Balb/c)F1 mice (H2bxd) exerted a significant GVL-effect with reduced relapse rate and improved survival in mice receiving the leukaemia cell line A20. In animals with low tumour load a significant reduction of the relapse rate from 82% following syngeneic BMT to 47% following allogeneic, GVH-nonreactive BMT could be achieved. Depletion of natural killer (NK) cells from the GVL-reactive semi-allogenic bone marrow graft enhances the relapse rate of the leukaemia A20 to 65%. In mice bearing the leukaemias WEHI-3 or PU5-1R allogeneic GVH-nonreactive BMT did not improve survival compared to syngeneic BMT. Transplantation of GVH-reactive bone marrow from DBA mice (MHC identical to Balb/c, minor difference) caused only a limited and insignificant reduction of relapse rate for animals with the leukaemia A20. These in vivo data are in close correlation with in vitro natural killer cell (NK) activity of the donor strains against the respective leukaemia targets. Depletion of NK cells from the GVL-reactive (C57 x Balb/c)F1 bone marrow resulted in a significant loss of GVL activity. We conclude that NK cells are involved in graft-versus-leukaemia effects independent of graft-versus-host disease (GVHD).
authors.affiliation: Department of Internal Medicine II, University of Kiel, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Glass
authors.forename: L
authors.initials: L
authors.lastname: Uharek
authors.forename: M
authors.initials: M
authors.lastname: Zeis
authors.forename: H
authors.initials: H
authors.lastname: Loeffler
authors.forename: W
authors.initials: W
authors.lastname: Mueller-Ruchholtz
authors.forename: W
authors.initials: W
authors.lastname: Gassmann
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D006087:Graft vs Host Reaction / Q000276:immunology*; D015448:Leukemia, B-Cell / Q000276:immunology*; D007951:Leukemia, Myeloid / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured