title: Allogeneic MHC-mismatched activated natural killer cells administered after bone marrow transplantation provide a strong graft-versus-leukaemia effect in mice.
abstract: Allogeneic lymphocytes administered with an unmanipulated bone marrow transplant provide a strong antileukaemic effect, the so-called graft-versus-leukaemia (GVL) effect. On the other hand, T-cell-mediated graft-versus-host-disease (GVHD) observed after transplantation of unmanipulated BM graft causes substantial morbidity and mortality. The aim of the present study was to determine the antileukaemic potential of enriched IL-2 activated NK cells administered 2 h after BMT. Balb/c (H-2d) mice were given a dose of A20 (H-2d, B-cell leukaemia) cells 2 d prior to lethal total body irradiation (TBI) and transplantation of either syngeneic or allogeneic anti-Thy1.2 (CD90) depleted bone marrow cells. Either syngeneic (Balb/c, H-2d) or allogeneic (C57BL/6, H-2b) enriched and IL-2 (200 U/ml for 24 h) activated NK cells were given 2 h after BMT. Injection of A20 leukaemia into normal Balb/c recipients led to death after a median of 14 d. A lethal dose of TBI followed by either syngeneic or allogeneic Thy1.2-depleted BMT resulted in a modest antileukaemic effect. The adoptive transfer of syngeneic enriched and IL-2 preincubated NK cells given at time of BMT exerted a significantly better GVL effect. However, the infusion of allogeneic enriched NK cells resulted in a stronger GVL effect. These results clearly demonstrate that allogeneic NK cells are superior to syngeneic NK cells in their potential to eradicate residual leukaemia cells after BMT without mediating clinical overt GVHD. This experimental setting may offer a strategy for treatment of haematological malignancies in a phase of minimal residual disease.
authors.affiliation: Department of Internal Medicine II, University of Kiel, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Zeis
authors.forename: L
authors.initials: L
authors.lastname: Uharek
authors.forename: B
authors.initials: B
authors.lastname: Glass
authors.forename: J
authors.initials: J
authors.lastname: Steinmann
authors.forename: P
authors.initials: P
authors.lastname: Dreger
authors.forename: W
authors.initials: W
authors.lastname: Gassmann
authors.forename: N
authors.initials: N
authors.lastname: Schmitz
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D006086:Graft vs Host Disease / Q000209:etiology; D006087:Graft vs Host Reaction; D007694:Killer Cells, Natural / Q000637:transplantation*; D015448:Leukemia, B-Cell / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D014184:Transplantation, Homologous