A humanized mouse model to study mast cells mediated cutaneous adverse drug reactions

Andrea Mencarelli, Merry Gunawan, Kylie Su Mei Yong, Pradeep Bist, Wilson Wei Sheng Tan, Sue Yee Tan, Min Liu, Edwin Kunxiang Huang, Yong Fan, Jerry Kok Yen Chan, Hae Woong Choi, Soman N. Abraham, Qingfeng Chen

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Recently a G-protein-coupled receptor, MAS Related GPR Family Member X2 (MRGPRX2), was identified as a specific receptor on human mast cells responsible for IgE independent adverse drug reactions (ADR). Although a murine homologue, Mrgprb2, has been identified for this receptor, its affinity for many ADR-causing drugs is poor making it difficult to undertake in vivo studies to examine mechanisms of ADR and to develop therapeutic strategies. Here, we have created humanized mice capable of generating MRGPRX2-expressing human MCs allowing for the study of MRGPRX2 MCs-mediated ADR in vitro as well as in vivo. Humanized mice were generated by hydrodynamic-injection of plasmids expressing human GM-CSF and IL-3 into NOD-scid IL2R-γ−/− strain of mice that had been transplanted with human hematopoietic stem cells. These GM/IL-3 humice expressed high numbers of tissue human MCs but the MRGPRX2 receptor expressed in MCs were limited to few body sites including the skin. Importantly, large numbers of MRGPRX2-expressing human MCs could be cultured from the bone marrow of GM/IL-3 humice revealing these mice to be an important source of human MCs for in vitro studies of MRGPRX2-related MCs activities. When GM/IL-3 humice were exposed to known ADR causing contrast agents (meglumine and gadobutrol), the humice were found to experience anaphylaxis analogous to the clinical situation. Thus, GM/IL-3 humice represent a valuable model for investigating in vivo interactions of ADR-causing drugs and human MCs and their sequelae, and these mice are also a source of human MRGPRX2-expressing MCs for in vitro studies.

Original languageEnglish
Pages (from-to)797-807
Number of pages11
JournalJournal of Leukocyte Biology
Volume107
Issue number5
DOIs
Publication statusPublished - 2020 May 1

Keywords

  • contrast agents
  • mast cells
  • MRGPRX2 receptor
  • non-immune adverse drug reactions
  • pseudoallergy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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