A Model for Personalized in Vivo Analysis of Human Immune Responsiveness

Kalscheuer, Hannes; Danzl, Nichole; Onoe, Takashi; Faust, Ted; Winchester, Robert; Goland, Robin; Greenberg, Ellen; Spitzer, Thomas R.; Savage, David G.; Tahara, Hiroyuki; Choi, Goda; Yang, Yong‐Guang; Sykes, Megan

doi:10.1126/scitranslmed.3003481

Cited by 111 publications

(126 citation statements)

References 48 publications

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“…On the same day, a piece of a partially HLA-matched cryopreserved and thawed fetal thymus was implanted under the kidney capsule of the animals. As previously shown, 10 human immune cells were detectable in PB 4 weeks after transplantation ( Figure 1A). B and T cells were the main human cell populations observed, with the former peaking around 10% of peripheral blood mononuclear cells (PBMCs) at week 12 and then slowly declining.…”

Section: Resultssupporting

confidence: 57%

“…Fetal thymus fragments were cryopreserved in 10% dimethyl sulfoxide (Sigma-Aldrich) and 90% human AB serum (Gemini Bio Products). 10 FL fragments were treated for 20 minutes at 37°C with 100 mg/mL of Liberase (Roche) to obtain a cell suspension. Human CD34 1 cells were purified from FL or BM by density gradient centrifugation (Histopaque-1077, Sigma) followed by positive immunomagnetic selection using anti-human CD34 microbeads (Miltenyi Biotec) according to the manufacturer's instructions.…”

Section: Animals and Human Tissues And Cellsmentioning

confidence: 99%

“…We recently modified a humanized mouse model that involves transplanting human fetal thymus tissue and fetal liver (FL)-derived hematopoietic stem cells (HSCs) to immunodeficient mice [4][5][6][7][8][9] to allow the study of immune development in HSCs from adults. 10 We have termed this the personalized immune (PI) mouse model. By reconstituting immunodeficient mice with bone marrow (BM)-derived HSCs from adults with established disease, we aimed to identify HSC-intrinsic abnormalities in immune regulation and development because some autoimmune diseases are transferable by HSCs.…”

Section: Introductionmentioning

confidence: 99%

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HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

et al. 2017

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Key Points• Increased human B-cell reconstitution is seen in female compared to male mice in multiple humanized mouse models.• The PI mouse model recapitulates HSCintrinsic autoimmune defects from T1D and RA bone marrow donors.B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females.Moreover, immune responses tend to be stronger in female vs male humans and mice.Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (

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Section: Resultssupporting

confidence: 57%

Section: Animals and Human Tissues And Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

et al. 2017

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“…Kalscheuer et al demonstrated that injection of human HSCs from bone marrow of adults, along with implantation of HLA-matched human fetal thymic tissue into immunodeficient mice, resulted in functional T cell, B cell, and myeloid cell reconstitution (36). Specifically, newly generated T cells were self tolerant and had a diverse repertoire.…”

Section: Finding the Perfect Castmentioning

confidence: 99%

New cast for a new era: preclinical cancer drug development revisited

Herter-Sprie

Kung²,

Wong³

2013

J. Clin. Invest.

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Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes.

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“…38 Bone marrow analysis revealed that POM treatment significantly induced the formation of granulocyte/ macrophage progenitor cells (CD34…”

mentioning

confidence: 99%

IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation

Wang

et al. 2018

Blood Advances

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Key Points• IMiD compounds cause selective ubiquitination and degradation of IKZF1 in CD34 1 cells by the CRBN E3 ubiquitin ligase.• Loss of IKZF1 is associated with a decrease of PU.1, critical for the development and maturation of neutrophils.We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia.The mechanism of action is unknown. Here we found that IMiD compounds cause selective

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A Model for Personalized in Vivo Analysis of Human Immune Responsiveness

Abstract: Personalized humanized mice can model intrinsic defects in human immune disease.

Cited by 111 publications

References 48 publications

HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

HSC extrinsic sex-related and intrinsic autoimmune disease–related human B-cell variation is recapitulated in humanized mice

New cast for a new era: preclinical cancer drug development revisited

IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation

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