Gene Therapy with an Adeno-Associated Viral Vector Expressing Human Interleukin-2 Alters Immune System Homeostasis in Humanized Mice

Durost, Philip A.; Aryee, Ken Edwin; Manzoor, Fatima; Tisch, Roland; Mueller, Christian; Jurczyk, Agata; Shultz, Leonard D.; Brehm, Michael A.

doi:10.1089/hum.2017.072

Cited by 16 publications

(13 citation statements)

References 87 publications

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“…3), we next determined whether administration of human recombinant IL-2 could modulate the T cell populations. We have previously shown that administration of a dsAAV8 vector encoding human IL-2 (dsAAV8-huIL-2) increased human regulatory T (T reg ) cells in NSG mice humanized by engraftment of human fetal liver and thymus [i.e., the BLT model (49)]. In the current study, injection of dsAAV8-huIL-2 led to a transient expansion of human CD45 + cells in the blood of NSG and NSG-(K b D b ) null (IA null ) mice engrafted with 10 3 10 6 PBMCs for 2 wk (Fig.…”

Section: Engrafted Human T Cells In Nsg-mentioning

confidence: 99%

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

et al. 2018

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Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T‐cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft‐versus‐host disease (GVHD) due to human T‐cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD‐scid IL‐2 receptor subunit γ (IL2rg)null (NSG) strains that lack murine MHC class I and II [NSG–β‐2‐microglobulin (B2M)null (IA IE)null and NSG‐(Kb Db)null (IAnull)]. We observed rapid human IgG clearance in NSG‐B2Mnull (IA IE)null mice whereas clearance in NSG‐(Kb Db)null (IAnull) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long‐term engraftment of human CD4+ and CD8+ T cells without acute GVHD. Engrafted human T‐cell function was documented by rejection of human islet allografts. Administration of human IL‐2 to NSG‐(Kb Db)null (IAnull) mice via adeno‐associated virus vector increased human CD45+ cell engraftment, including an increase in human regulatory T cells. However, high IL‐2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.—Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression. FASEB J. 33, 3137–3151 (2019). http://www.fasebj.org

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Section: Engrafted Human T Cells In Nsg-mentioning

confidence: 99%

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

et al. 2018

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“…34,35 Because human T cells are educated in autologous thymic tissues in the BLT model, it has been important in the investigation of human T cell development. 36,37 Furthermore, this model has had a great impact on the study of infectious diseases, especially HIV, as this model improves the colonization of lymphoid organs, together with the human reconstitution of the mucosal and gastrointestinal tracts. 35 In this model, BLT mice can recapitulate mucosal transmission of HIV via vaginal and rectal routes.…”

Section: Zeng Et Al 21mentioning

confidence: 99%

Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology

et al. 2019

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Significant advances in immunotherapies have resulted in the increasing need of predictive preclinical models to improve immunotherapeutic drug development, treatment combination, and to prevent or minimize toxicity in clinical trials. Immunodeficient mice reconstituted with human immune system (HIS), termed humanized mice or HIS mice, permit detailed analysis of human immune biology, development, and function. Although this model constitutes a great translational model, some aspects need to be improved as the incomplete engraftment of immune cells, graft versus host disease and the lack of human cytokines and growth factors. In this review, we discuss current HIS platforms, their pathology, and recent advances in their development to improve the quality of human immune cell reconstitution. We also highlight new technologies that can be used to better understand these models and how improved characterization is needed for their application in immuno-oncology safety, efficacy, and new modalities therapy development.

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“…Furthermore, adeno‐associated virus delivery of human IL‐2 has been demonstrated to increase the engraftment of regulatory T cells in NSG‐BLT mice . Notably, however, in certain background strains there is already an unphysiologically high proportion of T regulatory cells, which can be undesirable when investigating responses to infections (Table ).…”

Section: Adaptive Immunity In Humanized Micementioning

confidence: 99%

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

2018

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SummaryHumanized mice are increasingly appreciated as an incredibly powerful platform for infectious disease research. The often very narrow species tropism of many viral infections, coupled with the sometimes misleading results from preclinical studies in animal models further emphasize the need for more predictive model systems based on human cells rather than surrogates. Humanized mice represent such a model and have been greatly enhanced with regards to their immune system reconstitution as well as immune functionality in the past years, resulting in their recommendation as a preclinical model by the US Food and Drug Administration. This review aims to give a detailed summary of the generation of human peripheral blood lymphocyte‐, CD34+ haematopoietic stem cell‐ and bone marrow/liver/thymus‐reconstituted mice and available improved models (e.g. myeloid‐ or T‐cell‐only mice, MISTRG, NSG‐SGM3). Additionally, we summarize human‐tropic viral infections, for which humanized mice offer a novel approach for the study of disease pathogenesis as well as future perspectives for their use in biomedical, drug and vaccine research.

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Gene Therapy with an Adeno-Associated Viral Vector Expressing Human Interleukin-2 Alters Immune System Homeostasis in Humanized Mice

Cited by 16 publications

References 87 publications

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

Recent Advancements and Applications of Human Immune System Mice in Preclinical Immuno-Oncology

A Hitchhiker's guide to humanized mice: new pathways to studying viral infections

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