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

Paul J Bryce; Rustom Falahati; Laurie L. Kenney; John Leung; Christopher Bebbington; Nenad Tomasevic; Rebecca A. Krier; Chia Lin Hsu; Leonard D. Shultz; Dale L. Greiner; Michael A. Brehm

doi:10.1016/j.jaci.2016.01.049

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

Paul J Bryce, Rustom Falahati, Laurie L. Kenney, John Leung, Christopher Bebbington, Nenad Tomasevic, Rebecca A. Krier, Chia Lin Hsu, Leonard D. Shultz, Dale L. Greiner, Michael A. Brehm^*

^*Corresponding author for this work

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

82 Scopus citations

Abstract

Background 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^null SCF/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.

Original language	English (US)
Pages (from-to)	769-779
Number of pages	11
Journal	Journal of Allergy and Clinical Immunology
Volume	138
Issue number	3
DOIs	https://doi.org/10.1016/j.jaci.2016.01.049
State	Published - Sep 1 2016

Funding

Disclosure of potential conflict of interest: P. J. Bryce has a board membership with Clinical & Experimental Allergy and has received a grant from the National Institutes of Health. R. Falahati is employed by, has patents through, and has stock/stock options in Allakos. L. Kenney has received grants from the National Institutes of Health (grant no. 1R24 OD018259) and the Jackson Laboratory. J. Leung is employed by Allakos. C. Bebbington is employed by and has stock ownership in Allakos. N. Tomasevic is employed by Allakos. L. D. Shultz has received a consulting fee or honorarium from Allakos. D. L. Greiner and M. A. Brehm have received grants from the National Institutes of Health (grant no. 1R24 OD018259-01) and the Jackson Laboratory and have received consulting fees or honoraria from Allakos and the Jackson Laboratory. The rest of the authors declare that they have no relevant conflicts of interest. This work was supported in whole or in part by the National Institutes of Health (grant nos. 2R01AI076456-06A1 and R01AI05839-06A1 to P.J.B. and 1R24 OD018259-01 to M.A.B., L.D.S., and D.L.G.). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Keywords

Mast cell
NSG
NSG-SGM3
PCA
PSA
humanized mice
passive cutaneous anaphylaxis
passive systemic anaphylaxis

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Bryce, P. J., Falahati, R., Kenney, L. L., Leung, J., Bebbington, C., Tomasevic, N., Krier, R. A., Hsu, C. L., Shultz, L. D., Greiner, D. L., & Brehm, M. A. (2016). Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis. Journal of Allergy and Clinical Immunology, 138(3), 769-779. https://doi.org/10.1016/j.jaci.2016.01.049

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title = "Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis",

abstract = "Background 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 IL2rgnull SCF/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.",

keywords = "Mast cell, NSG, NSG-SGM3, PCA, PSA, humanized mice, passive cutaneous anaphylaxis, passive systemic anaphylaxis",

author = "Bryce, {Paul J} and Rustom Falahati and Kenney, {Laurie L.} and John Leung and Christopher Bebbington and Nenad Tomasevic and Krier, {Rebecca A.} and Hsu, {Chia Lin} and Shultz, {Leonard D.} and Greiner, {Dale L.} and Brehm, {Michael A.}",

note = "Publisher Copyright: {\textcopyright} 2016 American Academy of Allergy, Asthma & Immunology",

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doi = "10.1016/j.jaci.2016.01.049",

language = "English (US)",

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AU - Bryce, Paul J

AU - Falahati, Rustom

AU - Kenney, Laurie L.

AU - Leung, John

AU - Bebbington, Christopher

AU - Tomasevic, Nenad

AU - Krier, Rebecca A.

AU - Hsu, Chia Lin

AU - Shultz, Leonard D.

AU - Greiner, Dale L.

AU - Brehm, Michael A.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Background 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 IL2rgnull SCF/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.

AB - Background 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 IL2rgnull SCF/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.

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KW - passive systemic anaphylaxis

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

Abstract

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