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Blood, 15 February 2001, Vol. 97, No. 4, pp. 1123-1130
TRANSPLANTATION
Prevention of lethal acute graft-versus-host disease in mice by
oral administration of T helper 1 inhibitor, TAK-603
Yue Lu,
Sumio Sakamaki,
Hiroyuki Kuroda,
Toshiro Kusakabe,
Yuichi Konuma,
Takehide Akiyama,
Akihito Fujimi,
Naofumi Takemoto,
Kyokusen Nishiie,
Takuya Matsunaga,
Yasuo Hirayama,
Junji Kato,
Shinichiro Kon,
Katsuhisa Kogawa, and
Yoshiro Niitsu
From the Fourth Department of Internal Medicine and the
First Department of Pathology, Sapporo Medical University School of
Medicine, Sapporo, Japan; Department of Hematology/Oncology, Cancer
Center, Sun Yat-sen University of Medical Sciences, Guangzhou, China.
Acute graft-versus-host diseases (GVHD) is a major cause of
morbidity and mortality in patients undergoing allogeneic bone marrow
transplantation (BMT). T helper 1 (Th1)-type cytokines such as
interferon- or tumor necrosis factor- have been implicated in the
pathogenesis of acute GVHD. TAK-603 is a new quinoline derivative,
which is now in clinical trials for use as a disease-modifying antirheumatic drug. In preclinical studies, it inhibited delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and
selectively suppressed Th1 cytokine production. Thus, the present study
was designed to investigate whether the Th1 inhibitor (TAK-603)
ameliorates lethal acute GVHD in a mouse model. Administration of
TAK-603 into BALB/c mice given 10 Gy total body irradiation followed by transplantation of bone marrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of
GVHD pathology in the liver, intestine, and skin. TAK-603 reduced not
only the production of Th1-type cytokines, but also the proportion of
Th1 cells in CD4+ helper T cells in this GVHD mouse
model. These results suggest that TAK-603 could be a potent
therapeutic agent for acute lethal GVHD.
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[Abstract]
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