A rapid, sensitive, and reproducible in vivo PBMC humanized murine model for determining therapeutic-related cytokine release syndrome
Authors
Ye, ChuntingYang, 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 ExcellenceDocument Type
Journal ArticlePublication Date
2020-08-09Keywords
cytokine release syndromecytokine 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
Metadata
Show full item recordAbstract
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.202001203RPermanent Link to this Item
http://hdl.handle.net/20.500.14038/27327PubMed ID
32772418Related Resources
ae974a485f413a2113503eed53cd6c53
10.1096/fj.202001203R