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 mo rtality in patients undergoing allogeneic bone marrow transplantation (BMT) . T helper 1 (Th1)-type cytokines such as interferon-gamma or tumor necrosi s factor-iv 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 inhibite d delayed-type hypersensitivity, but not Arthus-type reaction, in mice, and selectively suppressed Th1 cytokine production. Thus, the present study wa s designed to investigate whether the Th1 inhibitor (TAK-603) ameliorates l ethal acute GVHD in a mouse model. Administration of TAK-603 into BALB/c mi ce given 10 Gy total body irradiation followed by transplantation of bone m arrow and spleen cells from C57BL/6 mice markedly reduced the mortality in association with minimal signs of GVHD pathology in the liver, intestine, a nd 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 mou se model. These results suggest that TAK-603 could be a potent therapeutic agent for acute lethal GVHD.