NOD-scid IL2rgamma(null) mouse model of human skin transplantation and allograft rejection.
BACKGROUND
Transplantation of human skin on immunodeficient mice that support engraftment with functional human immune systems would be an invaluable tool for investigating mechanisms involved in wound healing and transplantation. Nonobese diabetic (NOD)-scid interleukin-2 gamma chain receptor (NSG) readily engraft with human immune systems, but human skin graft integrity is poor. In contrast, human skin graft integrity is excellent on CB17-scid bg (SCID.bg) mice, but they engraft poorly with human immune systems.


METHODS
Human skin grafts transplanted onto immunodeficient NSG, SCID.bg, and other immunodeficient strains were evaluated for graft integrity, preservation of graft endothelium, and their ability to be rejected after engraftment of allogeneic peripheral blood mononuclear cells.


RESULTS
Human skin transplanted onto NSG mice develops an inflammatory infiltrate, consisting predominately of host Gr1(+) cells, that is detrimental to the survival of human endothelium in the graft. Treatment of graft recipients with anti-Gr1 antibody reduces this cellular infiltrate, preserves graft endothelium, and promotes wound healing, tissue development, and graft remodeling. Excellent graft integrity of the transplanted skin includes multilayered stratified human epidermis, well-developed human vasculature, human fibroblasts, and passenger leukocytes. Injection of unfractionated, CD4 or CD8 allogeneic human peripheral blood mononuclear cell induces a rapid destruction of the transplanted skin graft.


CONCLUSIONS
NSG mice treated with anti-Gr1 antibody provide a model optimized for both human skin graft integrity and engraftment of a functional human immune system. This model provides the opportunity to investigate mechanisms orchestrating inflammation, wound healing, revascularization, tissue remodeling, and allograft rejection and can provide guidance for improving outcomes after clinical transplantation.
Racki
Waldemar J
WJ
Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Covassin
Laurence
L
Brehm
Michael
M
Pino
Stephen
S
Ignotz
Ronald
R
Dunn
Raymond
R
Laning
Joseph
J
Graves
Susannah K
SK
Rossini
Aldo A
AA
Shultz
Leonard D
LD
Greiner
Dale L
DL
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D004912:Erythrocytes / Q000502:physiology; D005434:Flow Cytometry; D006084:Graft Rejection / Q000473:pathology*; D006801:Humans; D017493:Leukocyte Common Antigens / Q000032:analysis; D017708:Leukocyte Transfusion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000172:deficiency*; D016038:Skin Transplantation / Q000379:methods* / Q000473:pathology; D013154:Spleen / Q000473:pathology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous; D014945:Wound Healing
D015703:Antigens, CD; D015375:Receptors, Interleukin-2; D017493:Leukocyte Common Antigens