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 (Il2r gamma(null)) readily engraft with human stem cells. Here we analyzed human peripheral blood mononuclear cells (PBMC) for their ability to engraft NOD-scid Il2r gamma(null) mice and established engraftment kinetics, optimal cell dose, and the influence of injection route. Even at low PBMC input, NOD-scid Il2r gamma(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 Il2r gamma(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 toss of human C-peptide. These data suggest that humanized NOD-scid Il2r gamma(null) mice may represent an important surrogate for investigating in vivo mechanisms of human islet allograft rejection. (c) 2007 Elsevier Inc. All rights reserved.