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.
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.
André
Maya C
MC
Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.
Erbacher
Annika
A
Gille
Christian
C
Schmauke
Vanessa
V
Goecke
Barbara
B
Hohberger
Alexander
A
Mang
Philippa
P
Wilhelm
Ayline
A
Mueller
Ingo
I
Herr
Wolfgang
W
Lang
Peter
P
Handgretinger
Rupert
R
Hartwig
Udo F
UF
D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D020544:Graft vs Leukemia Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency* / Q000235:genetics; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods / Q000473:pathology
D018952:Antigens, CD34; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit