A chimeric human–mouse model of Sjögren's syndrome

Young, Murray; Wu, Lai-Chu; Bruss, Michael; Kaffenberger, Benjamin H.; Hampton, J.; Bolon, Brad; Jarjour, Wael

doi:10.1016/j.clim.2014.10.004

Cited by 21 publications

(32 citation statements)

References 16 publications

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“…While these humanized mice gradually develop allogenic graft versus host disease, limiting their use for many therapy studies, the up-regulation of PD-1 during acute graft versus host disease made it possible to image the biodistribution of this immunotherapy target in our case (21). Similar to our findings, several research groups have reported that engrafted immune cells infiltrate the salivary glands and lacrimal glands in PBL mice (22–24). Thus, we expected that the PD-1 expressing T cells would localize in the salivary glands in PBL mice, thus verifying that our PD-1 tracer was effective for imaging of PD-1-expressing T cells in vivo .…”

Section: Discussionsupporting

confidence: 92%

Preclinical Pharmacokinetics and Biodistribution Studies of ⁸⁹Zr-Labeled Pembrolizumab

et al. 2016

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Pembrolizumab is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1) found on T and pro-B cells. Pembrolizumab prevents PD-1 ligation by both PD-L1 and PD-L2, preventing the immune dysregulation that otherwise occurs when T cells encounter cells expressing these ligands. Clinically, PD-1 blockade elicits potent anti-tumor immune responses and antibodies blocking PD-1 ligation, including pembrolizumab, have recently received federal drug administration approval for the treatment of advanced melanoma, renal cell cancer, and non-small cell lung cancer. Methods In this study, we evaluated the pharmacokinetics, biodistribution, and dosimetry of pembrolizumab in vivo, accomplished through radiolabeling with positron emitter zirconium-89 (89Zr). Positron emission tomography (PET) imaging was utilized to evaluate the whole-body distribution of 89Zr-Df-Pembrolizumab in two rodent models (mice and rats). Data obtained from PET scans and biodistribution studies were extrapolated to humans to estimate the dosimetry of the tracer. As a proof-of-concept, the biodistribution of 89Zr-Df-Pembrolizumab is further investigated in a humanized murine model. Results The tracer remained stable in blood circulation throughout the study and accumulated the greatest in liver and spleen tissues. Both mice and rats showed similar biodistribution and pharmacokinetics of 89Zr-Df-Pembrolizumab. In the humanized mouse model, T-cell infiltration into the salivary and lacrimal glands could be successfully visualized. Conclusion These data will augment our understanding of the pharmacokinetics and biodistribution of radiolabeled pembrolizumab in vivo, while providing detailed dosimetry data that may lead to better dosing strategies in the future. These findings further demonstrate the utility of noninvasive in vivo PET imaging to dynamically track T-cell checkpoint receptor expression and localization in a humanized mouse model.

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Section: Discussionsupporting

confidence: 92%

Preclinical Pharmacokinetics and Biodistribution Studies of ⁸⁹Zr-Labeled Pembrolizumab

et al. 2016

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“…Histological analysis showed signs of inflammation within the lacrimal and salivary glands of mice engrafted with SjS. These infiltrates were mostly CD4 + and a small population of CD8 + T cells and B cellsYoung et al (2015)Type I diabetesNSG-Ab o DR4 engrafted with CD4 + T cells pulsed with autoantigen-derived peptidesMice injected with autoantigen-reactive CD4 + T cells lines from diabetic donors demonstrated human T cells infiltration into mouse islets, insulitis, and increased levels of demethylated β-cell–derived DNA in the bloodstream and reduced levels of insulin stainingViehmann Milam et al (2014) SLE Systemic lupus erythematosus, SjS Sjogren’s syndrome, CNS central nervous system …”

Section: Models Of Human Diseases Established On Humanized Micementioning

confidence: 99%

Humanized Mice as Unique Tools for Human-Specific Studies

Yong

Her

Chen

2018

Arch. Immunol. Ther. Exp.

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With an increasing human population, medical research is pushed to progress into an era of precision therapy. Humanized mice are at the very heart of this new forefront where it is acutely required to decipher human-specific disease pathogenesis and test an array of novel therapeutics. In this review, “humanized” mice are defined as immunodeficient mouse engrafted with functional human biological systems. Over the past decade, researchers have been conscientiously making improvements on the development of humanized mice as a model to closely recapitulate disease pathogenesis and drug mechanisms in humans. Currently, literature is rife with descriptions of novel and innovative humanized mouse models that hold a significant promise to become a panacea for drug innovations to treat and control conditions such as infectious disease and cancer. This review will focus on the background of humanized mice, diseases, and human-specific therapeutics tested on this platform as well as solutions to improve humanized mice for future clinical use.

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“…In addition, these investigators observed the infiltration of significantly larger numbers of human CD4 + T cells into the salivary and lacriminal glands of the SS- vs HD-engrafted NSG mice. Although significantly larger numbers of human CD8 + T cells and B cells were observed in both glands in SS- vs. HD-engrafted animals, the absolute numbers of these lymphocytes were much smaller than those observed for CD4 + T cells (200). This inflammatory infiltrate correlated well with loss of target organ function as saliva production was significantly decreased by 36% at 4 weeks post transfer of SS-derived PBMCs.…”

Section: Use Of Humanized Mice To Study Autoimmune and Inflammatory Dmentioning

confidence: 67%

“…Because the pathology observed in these mouse models of SS do not reproduce some of the key alterations described in human disease, investigators are just beginning to explore the use of humanized mice to study the immuno-pathological mechanisms responsible for induction of this prevalent disease. In the first and only study reporting the use of humanized mice in SS investigations, Andrade and coworkers showed that adoptive transfer PBMCs obtained from SS donors into NSG mice resulted in increased serum levels of a variety of human inflammatory cytokines including IFN-γ, IL-17, Il-6 and TNFα when compared to NSG engrafted with healthy donor (HD) PBMCs (200). In addition, these investigators observed the infiltration of significantly larger numbers of human CD4 + T cells into the salivary and lacriminal glands of the SS- vs HD-engrafted NSG mice.…”

Section: Use Of Humanized Mice To Study Autoimmune and Inflammatory Dmentioning

confidence: 99%

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

Koboziev

Jones-Hall

Valentine

et al. 2015

Inflammatory Bowel Diseases

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Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases as well as assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically-effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient’s bedside, it is becoming increasingly apparent that the mouse immune system may not adequately recapitulate the immuno-pathological mechanisms observed in human diseases. Indeed, it is well-known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system in order to address important, human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hemato-lymphoid cells in mice would provide investigators with a relatively inexpensive, small animal model to study clinically-relevant mechanisms as well as facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss current challenges and possible solutions for utilizing these unique mouse models to define the human-specific immuno-pathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation.

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A chimeric human–mouse model of Sjögren's syndrome

Cited by 21 publications

References 16 publications

Preclinical Pharmacokinetics and Biodistribution Studies of ⁸⁹Zr-Labeled Pembrolizumab

Preclinical Pharmacokinetics and Biodistribution Studies of ⁸⁹Zr-Labeled Pembrolizumab

Humanized Mice as Unique Tools for Human-Specific Studies

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

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A chimeric human–mouse model of Sjögren's syndrome

Cited by 21 publications

References 16 publications

Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab

Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab

Humanized Mice as Unique Tools for Human-Specific Studies

Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases

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Product

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Preclinical Pharmacokinetics and Biodistribution Studies of ⁸⁹Zr-Labeled Pembrolizumab

Preclinical Pharmacokinetics and Biodistribution Studies of ⁸⁹Zr-Labeled Pembrolizumab