Interspecies transcriptome profiles of human T cell activation and liver inflammation in a xenogeneic graft-versus-host disease model

Abstract

Background: Xenogeneic transplantation induces acute graft-versus-host disease (aGvHD) and subsequent vital organ damage. Herein, we aimed to examine hepatic damage associated with aGvHD using histopathology and gene expression profiles. Methods: A xenografic GvHD model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD-scid IL2Rγnull (NSG) mice after busulfan conditioning. NSG mice were assigned to groups treated with saline (S group) or a combination of busulfan and PBMCs (BP group). Histological lesions and RNA sequencing analysis of gene profiles in the BP group (GvHD model) were compared with those in the P group. Results: Predominant T cell subsets (95 %) in the blood of the BP group were identified as cytotoxic CD8+ T cells (56 %) and helper CD4+ T cells (31 %). Symptoms of aGvHD, including hepatocyte necrosis, bile duct hyperplasia, and human T cell infiltration, were observed. Gene expression analysis revealed upregulation of Th1 and Th2 cell differentiation (STAT4, IL4R, and NFACT1), T cell receptor signaling pathway (CD226 and GBP1), IL-1 pathway (CCL3, NAIP, and IRAK4), cell cycle (CDCA5, CDCA8, MCM5, KNL1, BUB1B, FBXO5, and CENPE) in human cells. In mouse cells, Il1a, Ifngr, Tnfrsf, and Il6ra genes (cytokines or their receptors) and Icam, Vcam, and Endra genes (adhesion molecules) were upregulated, whereas genes related to chromosome condensation (H2ac and H2bc) and fatty acid/steroid metabolism (Fasn, Rdh, and Scd) were downregulated. Interspecies gene network analysis revealed that activated human T cells are associated with liver damage through inflammatory and metabolic pathways, accompanied by increased mouse cell adhesion molecules and cytokines. Conclusion: Our findings offer valuable insights into the pathophysiology and biomarkers of aGvHD and may contribute to the development of novel therapeutics.

Keywords

• Graft-versus-host disease
• Humanized mouse model
• T cell pathway
• Liver toxicity
• Transcriptome analysis