Natural killer cells as effector cells of graft-versus-leukemia activity in a murine transplantation model.
The transfer of cytotoxic effector cells reduces the risk of relapse after allogeneic BMT. Two murine leukemia cell lines, A20 (B lymphocytic) and WEHI-3 (myelomonocytic), were used to investigate antileukemic effector mechanisms operating independently from graft-versus-host disease (GVHD). Different results were obtained with the two leukemia models. After injection of A20 cells, the majority of Balb/c recipients treated with syngeneic BMT died due to leukemia relapse (89%). The transplantation of MHC-matched DBA marrow resulted in chronic GvHD but did not reduce the risk of relapse (86%). Grafting of MHC-mismatched (but GvH-nonreactive) marrow cells from (C57xBalb)F1 hybrids, however, led to a significantly lower relapse rate (47%, p < 0.05). In vitro testing revealed that F1 cells but not Balb/c or DBA cells exert NK cell activity against A20. The elimination of NK 1.1-positive cells from the graft reduced the antileukemic activity of (C57xBalb)F1 marrow against A20 in vivo. After injection of WEHI-3 leukemia cells, syngeneic BMT cured most of the recipients (62%) and transplantation of (C57xBalb)F1 marrow provided no additional benefit. In contrast to unmanipulated Balb/c and (C57xBalb)F1 cells, which showed no NK activity against WEHI-3 in vitro, IL-2 treated effector cells were highly cytotoxic. Transfer of IL-2 preincubated grafts significantly decreased the relapse rate of WEHI-3 (19 vs. 38%) after syngeneic and allogeneic BMT. Our data indicate that GvL activity can be separated from GvHD. In our murine model, GvL activity appears to depend more on the donors NK/LAK cell activity than on the presence or absence of GvHD.
Uharek
L
L
Department of Internal Medicine II, University of Kiel, Germany.
Glass
B
B
Gaska
T
T
Zeiss
M
M
Gassmann
W
W
Löffler
H
H
Müller-Ruchholtz
W
W
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000473:pathology*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000473:pathology*; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000473:pathology*; D007942:Leukemia, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D014407:Tumor Cells, Cultured
D007376:Interleukin-2