A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation.
We examined the effect of a hydroxamic acid-based matrix metalloproteinase inhibitor (KB-R7785), which we previously demonstrated to have a potent ameliorating effect on acute graft-versus-host disease (GVHD), and on the graft-versus-leukaemia (GVL) effect of allogeneic bone marrow transplantation (BMT). KB-R7785 was administered to (C57BL/6 x BALB/c) F1 (CBF1) mice that had been inoculated with IgE-producing B53 hybridoma cells of BALB/c origin as a model tumour, along with or without transplantation of C57BL/6 (B6) bone marrow cells and spleen cells (BMS). Administration of KB-R7785 without BMS significantly prolonged the survival of B53-inoculated CBF1 mice by inhibiting the infiltration of B53 cells into the liver and spleen. Transplantation of B6 BMS without KB-R7785 resulted in the death of most recipients due to acute GVHD while efficiently eliminating B53 cells. Administration of KB-R7785 along with B6 BMS resulted in a 50% survival of B53-inoculated CBF1 mice over 50 d without histological manifestations of acute GVHD or residual B53 cells. These results indicate the beneficial effects of KB-R7785 that inhibit tumour infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.
Hattori
K
K
Division of Haematology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Hirano
T
T
Miyajima
H
H
Yamakawa
N
N
Ikeda
S
S
Yoshino
K
K
Tateno
M
M
Oshimi
K
K
Kayagaki
N
N
Yagita
H
H
Okumura
K
K
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D005260:Female; D005434:Flow Cytometry; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000627:therapeutic use*; D014184:Transplantation, Homologous
D006877:Hydroxamic Acids; C107086:KB R7785; D011480:Protease Inhibitors; D005998:Glycine