Human peripheral blood CD4 T cell‐engrafted non‐obese diabetic‐ scid IL2r γ null H2‐Ab1 tm1Gru Tg (human leucocyte antigen D‐related 4) mice: a mouse model of human allogeneic graft‐ versus ‐host disease

Summary Graft‐ versus ‐host disease (GVHD) is a life‐threatening complication of human allogeneic haematopoietic stem cell transplantation. Non‐obese diabetic (NOD)‐ scid IL2r γ null (NSG) mice injected with human peripheral blood mononuclear cells (PBMC) engraft at high levels and develop a robust xenogeneic (xeno)‐GVHD, which reproduces many aspects of the clinical disease. Here we show that enriched and purified human CD4 T cells engraft readily in NSG mice and mediate xeno‐GVHD, although with slower kinetics compared to injection of whole PBMC. Moreover, purified human CD4 T cells engraft but do not induce a GVHD in NSG mice that lack murine MHC class II (NSG‐ H2‐Ab1 tm1Gru , NSG‐Ab ° ), demonstrating the importance of murine major histocompatibility complex (MHC) class II in the CD4‐mediated xeno‐response. Injection of purified human CD4 T cells from a DR4‐negative donor into a newly developed NSG mouse strain that expresses human leucocyte antigen D‐related 4 (HLA‐DR4) but not murine class II (NSG‐Ab ° DR4) induces an allogeneic GVHD characterized by weight loss, fur loss, infiltration of human cells in skin, lung and liver and a high level of mortality. The ability of human CD4 T cells to mediate an allo‐GVHD in NSG‐Ab ° DR4 mice suggests that this model will be useful to investigate acute allo‐GVHD pathogenesis and to evaluate human specific therapies.