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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2738-2747
Graft-Versus-Leukemia Effect and Graft-Versus-Host Disease Can Be
Differentiated by Cytotoxic Mechanisms in a Murine Model of
Allogeneic Bone Marrow Transplantation
Nobuhiro Tsukada,
Tetsuji Kobata,
Yoshifusa Aizawa,
Hideo Yagita, and
Ko Okumura
From the Department of Immunology, Juntendo University School of
Medicine, Tokyo, Japan; The 1st Department of Internal Medicine,
Niigata University School of Medicine, Niigata, Japan; and CREST (Core
Research for Evolutional Science and Technology) of Japan Science and
Technology Corp, (JST), Tokyo, Japan.
Allogeneic bone marrow transplantation (allo-BMT) is associated with
both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL)
effect. In the present study, we examined the contribution of cytotoxic
effector mechanisms, which are mediated by tumor necrosis factor-
(TNF-), Fas ligand (FasL), or perforin, to GVHD and GVL effect in a
murine BMT model. Bone marrow cells plus spleen cells (BMS) from
wild-type, FasL-defective, or perforin-deficient donors were
transferred into lethally irradiated recipients in the parent (C57BL/6)
to F1 (C57BL/6 × DBA/2) BMT model with or without prior inoculation
of DBA/2 leukemia L1210 or P815 mast cytoma cells. The effect of
anti-TNF- antibody administration was also examined. Whereas the
defect or blockade of each cytotoxic pathway could ameliorate lethal
acute GVHD, the GVL effect was differentially affected. The wild-type
BMS recipients died of acute GVHD within 50 days without residual
leukemia cells. The FasL-defective BMS recipients showed 60%<
survival over 80 days without acute GVHD or residual leukemia cells.
Administration of anti-TNF- antibody resulted in early leukemia
relapse and the recipients died within 25 days with massive leukemia
infiltration in the liver. The perforin-deficient BMS recipients died
within 60 days with residual leukemia cells. These results suggest that blockade of the Fas/FasL pathway could be used for ameliorating GVHD
without impairing GVL effect in allo-BMT.
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