Long-term human CD34+ stem cell-engrafted nonobese diabetic/SCID/IL-2Rγnull mice show impaired CD8+ T cell maintenance and a functional arrest of immature …
MC André, A Erbacher, C Gille… - The Journal of …, 2010 - journals.aai.org
MC André, A Erbacher, C Gille, V Schmauke, B Goecke, A Hohberger, P Mang, A Wilhelm…
The Journal of Immunology, 2010•journals.aai.orgAllogeneic 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-2Rγ null …
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-2Rγ null …
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-2Rγ 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.
Allogeneic hematopoietic stem cell transplantation (HSCT) using bone marrow (BM) or mobilized peripheral blood stem cells (PBSCs) represents an effective immunotherapy for the treatment of high-risk leukemia. Because< 30% of patients have a HLA-identical donor, transplantation of HLA-incompatible stem cells remains the therapy of choice (1). However, the extent of HLA mismatches that is beneficial remains a matter of debate. Whereas certain HLA mismatches have been shown to exert potent graft-versus-leukemia (GvL) reactivity mediated by alloreactive NK cells (2, 3), disparities at single or multiple HLA alleles increase the risk of severe graft-versus-host disease (4, 5) mediated by alloreactive donor T cells. T cell depletion is an effective means for reducing alloreactivity (6) and is mandatory for donors with one fully mismatched HLA haplotype (7). However, in this haploidentical setting, rigorous T cell depletion strongly reduces adoptive immunity to pathogens and abrogates donor T cell-mediated GvL immunity, resulting in higher mortality and relapse (8, 9). Therefore, we were interested in developing a donor-patient–specific HSCT xenotransplantation model to study new immunotherapeutic strategies for improving donor T lymphocyte and NK cell-mediated GvL immunity (2, 10, 11) in a HLA-defined situation using long-term (> 20 wk) humanized mice.
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