Pig islet xenograft rejection in a mouse model with an established human immune system.
BACKGROUND
Xenotransplantation from pigs provides a potential solution to the severe shortage of human pancreata, but strong immunological rejection prevents its clinical application. A better understanding of the human immune response to pig islets would help develop effective strategies for preventing graft rejection.


METHODS
We assessed pig islet rejection by human immune cells in humanized mice with a functional human immune system. Humanized mice were prepared by transplantation of human fetal thymus/liver tissues and CD34(+) fetal liver cells into immunodeficient mice. Islet xenograft survival/rejection was determined by histological analysis of the grafts and measurement of porcine C-peptide in the sera of the recipients.


RESULTS
In untreated humanized mice, adult pig islets were completely rejected by 4 weeks. These mice showed no detectable porcine C-peptide in the sera, and severe intra-graft infiltration by human T cells, macrophages, and B cells, as well as deposition of human antibodies. Pig islet rejection was prevented by human T-cell depletion prior to islet xenotransplantation. Islet xenografts harvested from T-cell-depleted humanized mice were functional, and showed no human cell infiltration or antibody deposition.


CONCLUSIONS
Pig islet rejection in humanized mice is largely T-cell-dependent, which is consistent with previous observations in non-human primates. These humanized mice provide a useful model for the study of human xenoimmune responses in vivo.
Tonomura
Noriko
N
Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Shimizu
Akira
A
Wang
Shumei
S
Yamada
Kazuhiko
K
Tchipashvili
Vaja
V
Weir
Gordon C
GC
Yang
Yong-Guang
YG
D000818:Animals; D002096:C-Peptide / Q000097:blood; D046528:Chimerism; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007107:Immune System / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D023421:Models, Animal; D013552:Swine / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
D002096:C-Peptide