Exacerbation of pathogenic Th17-cell-mediated cutaneous graft-versus-host-disease in human IL-1β and IL-23 transgenic humanized mice

Abstract

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-1β and IL-23 cytokines (hIL-1β/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-1β/23 Tg mice compared with non-Tg mice after human CD4⁺ T cell transplantation. In the skin of Tg mice, IL-17- and IFNγ-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-1β/23 Tg mice were therefore highly sensitive models for inducing cutaneous GVHD mediated by human pathogenic Th17 cells.

Keywords: Cutaneous GVHD; Humanized mice; Pathogenic Th17 cells.