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
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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. / André, Maya C; Erbacher, Annika; Gille, Christian; Schmauke, Vanessa; Goecke, Barbara; Hohberger, Alexander; Mang, Philippa; Wilhelm, Ayline; Müller, Ingo; Herr, Wolfgang; Lang, Peter; Handgretinger, Rupert; Hartwig, Udo F.
In: J IMMUNOL, Vol. 185, No. 5, 01.09.2010, p. 2710-20.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - 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
AU - André, Maya C
AU - Erbacher, Annika
AU - Gille, Christian
AU - Schmauke, Vanessa
AU - Goecke, Barbara
AU - Hohberger, Alexander
AU - Mang, Philippa
AU - Wilhelm, Ayline
AU - Müller, Ingo
AU - Herr, Wolfgang
AU - Lang, Peter
AU - Handgretinger, Rupert
AU - Hartwig, Udo F
PY - 2010/9/1
Y1 - 2010/9/1
N2 - 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.
AB - 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.
KW - Adult
KW - Animals
KW - Antigens, CD34
KW - CD8-Positive T-Lymphocytes
KW - Cell Death
KW - Cell Differentiation
KW - Cell Lineage
KW - Graft vs Leukemia Effect
KW - Hematopoietic Stem Cell Transplantation
KW - Humans
KW - Interleukin Receptor Common gamma Subunit
KW - K562 Cells
KW - Killer Cells, Natural
KW - Lymphocyte Culture Test, Mixed
KW - Mice
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Inbred NOD
KW - Mice, Knockout
KW - Mice, SCID
KW - Mice, Transgenic
KW - Transplantation, Heterologous
U2 - 10.4049/jimmunol.1000583
DO - 10.4049/jimmunol.1000583
M3 - SCORING: Journal article
C2 - 20668220
VL - 185
SP - 2710
EP - 2720
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 5
ER -