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 × 106 CD4+ 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. 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 × 106 CD4+ 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.