Paul J Bryce1, Rustom Falahati2, Laurie L Kenney3, John Leung2, Christopher Bebbington2, Nenad Tomasevic2, Rebecca A Krier1, Chia-Lin Hsu1, Leonard D Shultz4, Dale L Greiner3, Michael A Brehm5. 1. Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Ill. 2. Allakos Inc, San Carlos, Ill. 3. Diabetes Center of Excellence, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Mass. 4. Jackson Laboratory, Bar Harbor, Me. 5. Diabetes Center of Excellence, Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Mass. Electronic address: michael.brehm@umassmed.edu.
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.
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 humanIgE-dependent allergic responses. METHODS: This model is based on the NOD-scidIL2rg(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 humanallergic responses and to test new therapeutics before their advancement to the clinic.
Authors: Leonard D Shultz; James Keck; Lisa Burzenski; Sonal Jangalwe; Shantashri Vaidya; Dale L Greiner; Michael A Brehm Journal: Mamm Genome Date: 2019-03-07 Impact factor: 2.957
Authors: Bradford A Youngblood; Emily C Brock; John Leung; Rustom Falahati; Paul J Bryce; Jessica Bright; Jason Williams; Leonard D Shultz; Dale L Greiner; Michael A Brehm; Christopher Bebbington; Nenad Tomasevic Journal: Int Arch Allergy Immunol Date: 2019-08-09 Impact factor: 2.749
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