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, 2010journals.aai.org
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 …
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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