Humanized mouse models of genetic immune disorders and hematological malignancies

Tyagi, Rajeev K.; Li, Jing; Jacobse, Justin; Snapper, Scott B.; Shouval, Dror S.; Goettel, Jeremy A.

doi:10.1016/j.bcp.2019.113671

Cited by 5 publications

(6 citation statements)

References 112 publications

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“…Some patients with deleterious IL-10R mutations showed the development of B cell lymphoma and presented a barrier in assessing the potential role of this pathway in the regulation of B cell development [182,183]. Human immune cells recovered from reconstituted NSG mice were found non-responsive to the exogenous IL-10 treatment, and these observations were consistent with the results obtained by using peripheral blood mononuclear cells (PBMCs) from IBD patients [184]. Interestingly, NSG mice harboring transgene encoding human KITLG, GM-CSF, and IL3 (NSG-SGM3) injected with IL-10R1deficient PBMCs were seen susceptible to DSS-induced colitis compared to those receiving healthy control PBMCs.…”

Section: Humanized Mouse Modelssupporting

confidence: 80%

“…Fully reconstituted immunodeficient mice with CD34+ HSCs isolated from patients with IL-10R mutations are not suitable for assessing the therapeutic biologics aiming at developing interventional approaches against IBD. Human immune system repopulated mice (humanized mice) would be appropriate to screen gene therapy-based approaches for restoring IL-10R signaling [184,185].…”

Section: Humanized Mouse Modelsmentioning

confidence: 99%

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Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice

Negi

Saini

Tandel

et al. 2021

Cells

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Crohn’s disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. “Humanized” mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.

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Section: Humanized Mouse Modelssupporting

confidence: 80%

Section: Humanized Mouse Modelsmentioning

confidence: 99%

Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice

Negi

Saini

Tandel

et al. 2021

Cells

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“…However, their stemness declines with the age of the donor ( 15 , 16 ), resulting in lower engraftment potential ( 17 , 18 ). Of note, donor cells can be obtained from patients affected by diverse hematopoietic diseases, thereby providing small animal models of human diseases including genetic immune disorders or hematological malignancies ( 3 , 19 ).…”

Section: Introductionmentioning

confidence: 99%

Building the Next Generation of Humanized Hemato-Lymphoid System Mice

et al. 2021

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Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these “humanized” mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

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“…The major advantage of using the animal model is the presence of immune system which mimics the effect of immune response during disease development. Furthermore, in some animal models the immune system could be manipulated in ways that makes it possible to ascertain the contribution of specific immune components to disease outcome (23,24). Mice, rats, Ferrets and non-human primates are also used to study pathogenesis induced by viruses, bacteria, and parasites as well as in vaccine efficacy studies (22,(25)(26)(27), but cross-model interpretations are limited by the fact that these animal models may not represent similar disease pathogenesis due to inter species variation and genetic background.…”

Section: Animal Models For Viral Diseasesmentioning

confidence: 99%

Modeling Human Viral Diseases: Trials and Triumphs

Ayyavoo

2021

Front.Virol.

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Humanized mouse models of genetic immune disorders and hematological malignancies

Cited by 5 publications

References 112 publications

Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice

Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice

Building the Next Generation of Humanized Hemato-Lymphoid System Mice

Modeling Human Viral Diseases: Trials and Triumphs

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