A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene.
Immunodeficient NOD-scid mice bearing a targeted mutation in the IL2 receptor common gamma chain (Il2rgamma(null)) readily engraft with human stem cells. Here we analyzed human peripheral blood mononuclear cells (PBMC) for their ability to engraft NOD-scid Il2rgamma(null) mice and established engraftment kinetics, optimal cell dose, and the influence of injection route. Even at low PBMC input, NOD-scid Il2rgamma(null) mice reproducibly support high human PBMC engraftment that plateaus within 3-4 weeks. In contrast to previous stocks of immunodeficient mice, we observed low intra- and inter-donor variability of engraftment. NOD-scid Il2rgamma(null) mice rendered hyperglycemic by streptozotocin treatment return to normoglycemia following transplantation with human islets. Interestingly, these human islet grafts are rejected following injection of HLA-mismatched human PBMC as evidenced by return to hyperglycemia and loss of human C-peptide. These data suggest that humanized NOD-scid Il2rgamma(null) mice may represent an important surrogate for investigating in vivo mechanisms of human islet allograft rejection.
King
Marie
M
Department of Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01655, USA.
Pearson
Todd
T
Shultz
Leonard D
LD
Leif
Jean
J
Bottino
Rita
R
Trucco
Massimo
M
Atkinson
Mark A
MA
Wasserfall
Clive
C
Herold
Kevan C
KC
Woodland
Robert T
RT
Schmidt
Madelyn R
MR
Woda
Bruce A
BA
Thompson
Michael J
MJ
Rossini
Aldo A
AA
Greiner
Dale L
DL
D000818:Animals; D003920:Diabetes Mellitus / Q000276:immunology; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency* / Q000235:genetics*; D007515:Islets of Langerhans / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000637:transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
D053631:Interleukin Receptor Common gamma Subunit