Although Th17 cells are closely linked to cutaneous graft-versus-host-disease (GVHD) in mouse models, this association remains unclear in human GVHD. In this study, we established a novel xenogeneic cutaneous GVHD model using humanized mice. To induce the differentiation of human Th17 cells, we created transgenic NOG mice expressing human IL-1 beta and IL-23 cytokines (hIL-1 beta/23 Tg) and transplanted with human CD4(+) T cells. The pathologies of cutaneous GVHD, such as a decrease in body weight, alopecia, and T cell inflammation in the skin, were observed much earlier in hIL-1 beta/23 Tg mice compared with non-Tg mice after human CD4(+) T cell transplantation. In the skin of Tg mice, 1L-17- and 1FN gamma-producing pathogenic Th17 cells were significantly accumulated. Furthermore, high infiltration of murine neutrophils was seen in the skin of Tg mice, but not non-Tg mice, which may have been the cause of the severe alopecia. CD4(+) T-cell-transferred hIL-1 beta/23 Tg mice were therefore highly sensitive models for inducing cutaneous GVHD mediated by human pathogenic Th17 cells. (C) 2019 Elsevier Inc. All rights reserved.