title: 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.
abstract: 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.
authors.affiliation: Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karls University, Tuebingen, Germany.
authors.forename: Maya C
authors.initials: MC
authors.lastname: André
authors.forename: Annika
authors.initials: A
authors.lastname: Erbacher
authors.forename: Christian
authors.initials: C
authors.lastname: Gille
authors.forename: Vanessa
authors.initials: V
authors.lastname: Schmauke
authors.forename: Barbara
authors.initials: B
authors.lastname: Goecke
authors.forename: Alexander
authors.initials: A
authors.lastname: Hohberger
authors.forename: Philippa
authors.initials: P
authors.lastname: Mang
authors.forename: Ayline
authors.initials: A
authors.lastname: Wilhelm
authors.forename: Ingo
authors.initials: I
authors.lastname: Mueller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
authors.forename: Peter
authors.initials: P
authors.lastname: Lang
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Udo F
authors.initials: UF
authors.lastname: Hartwig
mesh_terms: 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
chemical_list: D018952:Antigens, CD34; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit