title: A Novel Xenogeneic Graft-Versus-Host Disease Model for Investigating the Pathological Role of Human CD4+or CD8+T Cells Using Immunodeficient NOG Mice.
abstract: Graft-versus-host disease (GVHD) is a major complication of allogenic bone marrow transplantation and involves the infiltration of donor CD4+and/or CD8+T cells into various organs of the recipient. The pathological role of human CD4+and CD8+T cells in GVHD remains controversial. In this study, we established two novel xenogeneic (xeno)-GVHD models. Human CD4+or CD8+T cells were purified from peripheral blood and were transplanted into immunodeficient NOD/Shi-scid IL2rgnull(NOG) mice. Human CD8+T cells did not induce major GVHD symptoms in conventional NOG mice. However, CD8+T cells immediately proliferated and induced severe GVHD when transferred into NOG mice together with at least 0.5 × 106CD4+T cells or into NOG human interleukin (IL)-2 transgenic mice. Human CD4+T cell-transplanted NOG mice developed skin inflammations including alopecia, epidermal hyperplasia, and neutrophilia. Pathogenic T helper (Th)17 cells accumulated in the skin of CD4+T cell-transplanted NOG mice. Further, an anti-human IL-17 antibody (secukinumab) significantly suppressed these skin pathologies. These results indicate that pathogenic human Th17 cells induce cutaneous GVHD via IL-17-dependent pathways. This study provides fundamental insights into the pathogenesis of xeno-GVHD, and these humanized mouse models may be useful as preclinical tools for the prevention of GVHD.
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Ito
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Katano
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yagoto
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ka
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ogura
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ito
mesh_terms: D000505:Alopecia / Q000276:immunology* / Q000473:pathology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic
chemical_list: C508717:IL17A protein, human; D020381:Interleukin-17
keywords: animal models: murine; basic (laboratory) research/science; bone marrow/hematopoietic stem; cell transplantation; graft-versus-host disease (GVHD); immunobiology; translational research/science; xenotransplantation