2. Academic Validation
  3. Bone marrow-liver-thymus (BLT) immune humanized mice as a model to predict cytokine release syndrome

Bone marrow-liver-thymus (BLT) immune humanized mice as a model to predict cytokine release syndrome

  • Transl Res. 2019 Aug:210:43-56. doi: 10.1016/j.trsl.2019.04.007.
Hangyi Yan 1,  Kenrick M Semple 2,  Carlos M Gonzaléz 3,  Kristina E Howard 4
Affiliations

Affiliations

  • 1 Division of Applied Regulatory Sciences, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland; Division of Immunology and Hematology Devices, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland.
  • 2 Division of Applied Regulatory Sciences, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland; Division of Gastroenterology and Inborn Errors Products, Office of New Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
  • 3 Division of Applied Regulatory Sciences, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland; Division of Drug Quality I, Office of Compliance, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland.
  • 4 Division of Applied Regulatory Sciences, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland. Electronic address: Kristina.Howard@fda.hhs.gov.
PMID: 31082370 DOI: 10.1016/j.trsl.2019.04.007
Abstract

Cytokine release syndrome (CRS) is a serious and potentially life-threatening complication that can be associated with biological drug products. In vitro assays or in vivo tests using nonhuman primates may fail to predict CRS due to species differences and the complexity of immune system. Therefore, model species that have human-specific immune components may improve the ability to identify CRS and enhance product safety. In this study we used bone marrow-liver-thymus (BLT) humanized mice to test muromonab (OKT3), an anti-CD3 antibody with a black box warning for CRS. Initially, we completed pilot and dose escalation studies with muromonab and showed that when the dose was increased sufficiently, BLT-humanized mice experienced serious adverse outcomes including moribundity. Full studies compared muromonab treatment with adalimumab, saline, and a group pretreated with methylprednisolone prior to muromonab. We evaluated immune cell activation using flow cytometry and cytokine expression using a custom 10-plex cytokine assay to assess levels of human TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-10, IL-13, IL-17A, IL12/23p40, and GM-CSF. Muromonab treated mice had significant increases in all cytokines tested with T-cell depletion and T-cell activation noted. Adalimumab (active) and saline (inactive) control groups did not demonstrate cytokine expression changes or alterations in T-cell numbers or activation. Further, pretreatment with methylprednisolone blunted or abrogated cytokine increases. This study demonstrates that BLT-humanized mice are capable of experiencing CRS, and could be used to screen biologics for this adverse event to enhance patient safety.

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