Long-term human CD34+ stem cell-engrafted nonobese diabetic/SCID/IL-2R gamma(null) mice show impaired CD8+ T cell maintenance and a functional arrest of immature NK cells

J Immunol. 2010 Sep 1;185(5):2710-20. doi: 10.4049/jimmunol.1000583. Epub 2010 Jul 28.


Allogeneic hematopoietic stem cell transplantation represents the most effective form of immunotherapy for chemorefractory diseases. However, animal models have been missing that allow evaluation of donor-patient-specific graft-versus-leukemia effects. Thus, we sought to establish a patient-tailored humanized mouse model that would result in long-term engraftment of various lymphocytic lineages and would serve as a donor-specific surrogate. Following transfer of donor-derived peripheral blood stem cells into NOD/SCID/IL-2Rgamma(null) (NSG) mice with supplementation of human IL-7, we could demonstrate robust engraftment and multilineage differentiation comparable to earlier studies using cord blood stem cells. Phenotypical and functional analyses of lymphoid lineages revealed that >20 wk posthematopoietic stem cell transplantation, the majority of T lymphocytes consisted of memory-type CD4(+) T cells capable of inducing specific immune functions, whereas CD8(+) T cells were only present in low numbers. Analysis of NSG-derived NK cells revealed the expression of constitutively activated CD56(bright)CD16(-) killer Ig-like receptor(negative) NK cells that exhibited functional impairments. Thus, the data presented in this study demonstrate that humanized NSG mice can be successfully used to develop a xenotransplantation model that might allow patient-tailored treatment strategies in the future, but also highlight the need to improve this model, for example, by coadministration of differentiation-promoting cytokines and induction of human MHC molecules to complement existing deficiencies in NK and CD8(+) T cell development.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antigens, CD34 / biosynthesis*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology*
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Differentiation / immunology*
  • Cell Lineage / immunology
  • Graft vs Leukemia Effect / immunology
  • Hematopoietic Stem Cell Transplantation / methods*
  • Humans
  • Interleukin Receptor Common gamma Subunit / deficiency*
  • Interleukin Receptor Common gamma Subunit / genetics
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Transplantation, Heterologous / immunology*
  • Transplantation, Heterologous / methods
  • Transplantation, Heterologous / pathology


  • Antigens, CD34
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit