Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603.
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-gamma or tumor necrosis factor-alpha 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.
Lu
Y
Y
Fourth Department of Internal Medicine and the First Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Sakamaki
S
S
Kuroda
H
H
Kusakabe
T
T
Konuma
Y
Y
Akiyama
T
T
Fujimi
A
A
Takemoto
N
N
Nishiie
K
K
Matsunaga
T
T
Hirayama
Y
Y
Kato
J
J
Kon
S
S
Kogawa
K
K
Niitsu
Y
Y
D000208:Acute Disease; D000284:Administration, Oral; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011828:Radiation Chimera; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000637:transplantation; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D014184:Transplantation, Homologous / Q000009:adverse effects; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D016207:Cytokines; D007166:Immunosuppressive Agents; D011804:Quinolines; D014230:Triazoles; C104411:TAK 603