title: Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603.
abstract: 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.
authors.affiliation: Fourth Department of Internal Medicine and the First Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Sakamaki
authors.forename: H
authors.initials: H
authors.lastname: Kuroda
authors.forename: T
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Y
authors.initials: Y
authors.lastname: Konuma
authors.forename: T
authors.initials: T
authors.lastname: Akiyama
authors.forename: A
authors.initials: A
authors.lastname: Fujimi
authors.forename: N
authors.initials: N
authors.lastname: Takemoto
authors.forename: K
authors.initials: K
authors.lastname: Nishiie
authors.forename: T
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Y
authors.initials: Y
authors.lastname: Hirayama
authors.forename: J
authors.initials: J
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Kon
authors.forename: K
authors.initials: K
authors.lastname: Kogawa
authors.forename: Y
authors.initials: Y
authors.lastname: Niitsu
mesh_terms: 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*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D011804:Quinolines; D014230:Triazoles; C104411:TAK 603