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    A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome

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    Authors
    Ye, Chunting
    Yang, Hongyuan
    Cheng, Mingshan
    Shultz, Leonard D.
    Greiner, Dale L.
    Brehm, Michael A.
    Keck, James G.
    UMass Chan Affiliations
    Program in Molecular Medicine, Diabetes Center of Excellence
    Document Type
    Journal Article
    Publication Date
    2020-08-09
    Keywords
    cytokine release syndrome
    cytokine storm
    humanized mouse
    immune toxicity
    therapeutic
    Disease Modeling
    Immunology of Infectious Disease
    Immunopathology
    Immunoprophylaxis and Therapy
    Immunotherapy
    Microbiology
    Pathological Conditions, Signs and Symptoms
    Virus Diseases
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    Link to Full Text
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436391/
    Abstract
    Immunotherapy is a powerful treatment strategy being applied to cancer, autoimmune diseases, allergies, and transplantation. Although therapeutic monoclonal antibodies (mAbs) have demonstrated significant clinical efficacy, there is also the potential for severe adverse events, including cytokine release syndrome (CRS). CRS is characterized by the rapid production of inflammatory cytokines following delivery of therapy, with symptoms ranging from mild fever to life-threating pathology and multi-organ failure. Overall there is a paucity of models to reliably and accurately predict the induction of CRS by immune therapeutics. Here, we describe the development of a humanized mouse model based on the NOD-scid IL2rg(null) (NSG) mouse to study CRS in vivo. PBMC-engrafted NSG, NSG-MHC-DKO, and NSG-SGM3 mice were used to study cytokine release in response to treatment with mAb immunotherapies. Our data show that therapeutic-stimulated cytokine release in these PBMC-based NSG models captures the variation in cytokine release between individual donors, is drug dependent, occurs in the absence of acute xeno-GVHD, highlighting the specificity of the assay, and shows a robust response following treatment with a TGN1412 analog, a CD28 superagonist. Overall our results demonstrate that PBMC-engrafted NSG models are rapid, sensitive, and reproducible platforms to screen novel therapeutics for CRS.
    Source

    Ye C, Yang H, Cheng M, Shultz LD, Greiner DL, Brehm MA, Keck JG. A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome. FASEB J. 2020 Aug 9:10.1096/fj.202001203R. doi: 10.1096/fj.202001203R. Epub ahead of print. PMID: 32772418; PMCID: PMC7436391. Link to article on publisher's site

    DOI
    10.1096/fj.202001203R
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/27327
    PubMed ID
    32772418
    Related Resources

    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1096/fj.202001203R
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