Making HIS mice more human-like

Simpson, John; Brown, Matthew E.

doi:10.1002/jlb.5ce1019-262r

Cited by 3 publications

(3 citation statements)

References 12 publications

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“…Other additive hypoimmune editing approaches may be needed, such as a promising CD64 overexpression strategy recently described by Gravina et al 51 Relatedly, better in vitro and in vivo models of human antibody-mediated rejection are needed to adequately interrogate these types of research questions. Humanized mouse models are quite useful for T cell-mediated rejection and natural killer cell-mediated allorejection studies, [64][65][66][67] but the most commonly used humanized mice are suboptimal for antibody-mediated rejection studies due to B cell immaturity and impeded class switching in de novo antibodies. 68 Our group and others are working on new iterations of humanized mouse models that incorporate more robust T cell, natural killer cell, and innate immune cell repertoires in order to improve their utility for transplantation immunology-focused research studies, and creation of tractable models harboring antigen-specific IgG antibody pools is an area of intense focus.…”

Section: Discussionmentioning

confidence: 99%

Diminished Immune Cell Adhesion in Hypoimmune ICAM-1 Knockout Pluripotent Stem Cells

Saha,

Haynes,

Del Rio

et al. 2024

Preprint

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Hypoimmune gene edited human pluripotent stem cells (hPSCs) are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive (e.g., T cell) immune responses, but have largely not addressed the innate immune cells (e.g., monocytes, neutrophils) that mediate inflammation and rejection processes occurring early after graft transplantation. We identified the adhesion molecule ICAM-1 as a novel hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In a series of studies, we found that ICAM-1 blocking or knock-out (KO) in hPSC-derived cardiovascular therapies imparted significantly diminished binding of multiple immune cell types. ICAM-1 KO resulted in diminished T cell proliferation responsesin vitroand in longerin vivoretention/protection of KO grafts following immune cell encounter in NeoThy humanized mice. The ICAM-1 KO edit was also introduced into existing first-generation hypoimmune hPSCs and prevented immune cell binding, thereby enhancing the overall hypoimmune capacity of the cells. This novel hypoimmune editing strategy has the potential to improve the long-term efficacy and safety profiles of regenerative therapies for cardiovascular pathologies and a number of other diseases.HighlightsAntibody blocking of ICAM-1 on human pluripotent stem cell-derived cells inhibits immune cell adhesionCRISPR/Cas9 knock-out of ICAM-1 ablates surface and secreted ICAM-1 protein and inhibits immune adhesionICAM-1 knock-out results in decreased T cell proliferative responses to human pluripotent stem cell-derived graftsin vitro, and resistance to immune-mediated graft lossin vivoAddition of ICAM-1 knock-out to first generation MHC knock-out human pluripotent stem cells confers protection against immune adhesionGraphical AbstractICAM-1 Knock-out in Transendothelial Migration and at the Immune Synapse.Abbreviations: PSC-EC – pluripotent stem cell-derived endothelial cells; KO – knock-out; dSMAC – distal supramolecular activation complex; pSMAC – peripheral supramolecular activation complex; cSMAC – central supramolecular activation complex.

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Section: Discussionmentioning

confidence: 99%

Diminished Immune Cell Adhesion in Hypoimmune ICAM-1 Knockout Pluripotent Stem Cells

Saha,

Haynes,

Del Rio

et al. 2024

Preprint

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“…It is therefore important to choose carefully both the appropriate tissues and mouse strains for your experiments. We have discussed this topic in previous publications (McIntosh & Brown, 2015; Simpson & Brown, 2020). We recommend that every researcher who is beginning to work with humanized mice consult the article by Shultz et al.…”

Section: Humanized Mice Varieties and Recommendations For Hpsc Studiesmentioning

confidence: 99%

“…It is therefore important to choose carefully both the appropriate tissues and mouse strains for your experiments. We have discussed this topic in previous publications Simpson & Brown, 2020). We recommend that every researcher who is beginning to work with humanized mice consult the article by Shultz et al (2012) in Nature Reviews Immunology for an introduction to these The four types of humanized mice that we recommend for PSC studies are:…”

Section: Step 1: Choice Of Mouse Host Strainmentioning

confidence: 99%

Humanized Mouse Models for Evaluation of PSC Immunogenicity

Hermsen¹,

Brown²

2020

CP Stem Cell Biology

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New human pluripotent stem cell (hPSC)‐derived therapies are advancing to clinical trials at an increasingly rapid pace. In addition to ensuring that the therapies function properly, there is a critical need to investigate the human immune response to these cell products. A robust allogeneic (or autologous) immune response could swiftly eliminate an otherwise promising cell therapy, even in immunosuppressed patients. In coming years, researchers in the regenerative medicine field will need to utilize a number of in vitro and in vivo assays and models to evaluate and better understand hPSC immunogenicity. Humanized mouse models—mice engrafted with functional human immune cell types—are an important research tool for investigating the mechanisms of the adaptive immune response to hPSC therapies. This article provides an overview of humanized mouse models relevant to the study of hPSC immunogenicity and explores central considerations for investigators seeking to utilize these powerful models in their research. © 2020 Wiley Periodicals LLC.

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