Humanised mice have functional human neutrophils

The differences between murine and human neutrophils mean that findings in mice may not translate to humans, and therefore an in vivo model with human neutrophils would be an important methodological advance. We generated humanised mice by injecting human cord blood derived CD34+ stem cells into irradiated NOD-scid-γc−/− mice. At least 3months after engraftment, treatment of mice with GCSF mobilised circulating human neutrophils, which comprised 2.6% of human leukocytes, and led to L-selectin shedding and upregulation of CD66b, CD11b and CD63. Subsequent in vivo LPS treatment led to further downregulation of L-selectin with upregulation of CD66b and CD63, and also resulted in human neutrophil sequestration in the lungs. Furthermore, human neutrophils from these mice were capable of robust functional responses. They were shown to undergo a respiratory burst, and to degranulate with upregulation of CD63 and CD66b, in response to fMLP and Escherichia coli. These data show that functional human neutrophils develop from CD34+ cord blood stem cells in NOD-scid-γc−/− mice. They suggest that this approach may facilitate the in vivo study of human neutrophils in clinically relevant models of infection and autoimmunity.