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 3 months 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.
King's College London, King's Health Partners, Medical Research Council Centre for Transplantation, Guy's Hospital, London SE1 9RT, UK.
Alice M
AM
Coughlan
Simon J
SJ
Freeley
Michael G
MG
Robson
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D018952:Antigens, CD34 / Q000276:immunology* / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D060149:Tetraspanin 30 / Q000276:immunology / Q000378:metabolism; D014183:Transplantation, Heterologous
D015703:Antigens, CD; D018952:Antigens, CD34; D039481:CD11b Antigen; C504120:CEACAM8 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D053631:Interleukin Receptor Common gamma Subunit; D008070:Lipopolysaccharides; D060149:Tetraspanin 30; D019041:L-Selectin; D016179:Granulocyte Colony-Stimulating Factor