A humanized mouse model to study human immune response in xenotransplantation.
BACKGROUND
A major barrier to the clinical application of xenotransplantation as a treatment option for patients is T cell-mediated rejection. Studies based on experimental rodent models of xenograft tolerance or rejection in vivo have provided useful information about the role of T cell immune response in xenotransplantation. However not all observations seen in rodents faithfully recapitulate the human situation. This study aimed to establish a humanized mouse model of xenotransplantation, which mimics xenograft rejection in the context of the human immune system.


METHODS
NOD-SCID IL2rgamma-/- mice were transplanted with neonatal porcine islet cell clusters (NICC) followed by reconstitution of human peripheral blood mononuclear cells (PBMC). Human leukocyte engraftment and islet xenograft rejection were confirmed by flow cytometric and histological analyses.


RESULTS
In the absence of human PBMC, porcine NICC transplanted into NOD-SCID IL2rgamma-/- mice revealed excellent graft integrity and endocrine function. Human PBMC demonstrated a high level of engraftment in NOD-SCID IL2rgamma-/- mice. Reconstitution of NICC recipient NOD-SCID IL2rgamma-/- mice with human PBMC led to the rapid destruction of NICC xenografts in a PBMC number-dependent manner.


CONCLUSIONS
Human PBMC-reconstituted NOD-SCID IL2rgamma-/- mice provide an ideal model to study human immune responses in xenotransplantation. Studies based on this humanized mouse model will provide insight for improving the outcomes of clinical xenotransplantation.
Center for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Westmead, NSW, Sydney 2145, Australia.
Ming
M
Ji
Xi
X
Jin
Peta
P
Phillips
Shounan
S
Yi
D000818:Animals; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023421:Models, Animal; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit