Humanized mouse model of mast cell-mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis

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• 作者：Paul J. Bryce ; PhD^a ; ^&lowast ; ; Rustom Falahati ; PhD^b ; ^&lowast ; ; Laurie L. Kenney ; PhD^c ; John Leung ; BS^b ; Christopher Bebbington ; PhD^b ; Nenad Tomasevic ; PhD^b ; Rebecca A. Krier ; MS^a ; ^&lowast ; ; Chia-Lin Hsu ; PhD^a ; ^&lowast ; ; Leonard D. Shultz ; PhD^d ; Dale L. Greiner ; PhD^c ; Michael A. Brehm ; PhD^c ; ^{michael.brehm@umassmed.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Mast cell ; humanized mice ; NSG ; NSG-SGM3 ; passive cutaneous anaphylaxis ; PCA ; passive systemic anaphylaxis ; PSA
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：138
• 期：3
• 页码：769-779
• 全文大小：2196 K

文摘

Mast cells are a critical component of allergic responses in humans, and animal models that allow the in vivo investigation of their contribution to allergy and evaluation of new human-specific therapeutics are urgently needed.

Objective

To develop a new humanized mouse model that supports human mast cell engraftment and human IgE-dependent allergic responses.

Methods

This model is based on the NOD-scid IL2rg^nullSCF/GM-CSF/IL3 (NSG-SGM3) strain of mice engrafted with human thymus, liver, and hematopoietic stem cells (termed Bone marrow, Liver, Thymus [BLT]).

Results

Large numbers of human mast cells develop in NSG-SGM3 BLT mice and populate the immune system, peritoneal cavity, and peripheral tissues. The human mast cells in NSG-SGM3 BLT mice are phenotypically similar to primary human mast cells and express CD117, tryptase, and FcεRI. These mast cells undergo degranulation in an IgE-dependent and -independent manner, and can be readily cultured in vitro for additional studies. Intradermal priming of engrafted NSG-SGM3 mice with a chimeric IgE containing human constant regions resulted in the development of a robust passive cutaneous anaphylaxis response. Moreover, we describe the first report of a human mast cell antigen-dependent passive systemic anaphylaxis response in primed mice.

Conclusions

NSG-SGM3 BLT mice provide a readily available source of human mast cells for investigation of mast cell biology and a preclinical model of passive cutaneous anaphylaxis and passive systemic anaphylaxis that can be used to investigate the pathogenesis of human allergic responses and to test new therapeutics before their advancement to the clinic.