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Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis  Paul J. Bryce, PhD, Rustom Falahati, PhD,

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Presentation on theme: "Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis  Paul J. Bryce, PhD, Rustom Falahati, PhD,"— Presentation transcript:

1 Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis  Paul J. Bryce, PhD, Rustom Falahati, PhD, Laurie L. Kenney, PhD, John Leung, BS, Christopher Bebbington, PhD, Nenad Tomasevic, PhD, Rebecca A. Krier, MS, Chia-Lin Hsu, PhD, Leonard D. Shultz, PhD, Dale L. Greiner, PhD, Michael A. Brehm, PhD  Journal of Allergy and Clinical Immunology  Volume 138, Issue 3, Pages (September 2016) DOI: /j.jaci Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Journal of Allergy and Clinical Immunology 2016 138, 769-779DOI: (10
Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 1 Human cells in the blood and peritoneal lavage of NSG-BLT and NSG-SGM3 BLT mice. The percentage and number of human cells in the blood and PECs 8 to 10 weeks after transplantation (A-I). J and K, Representative histograms. L, Siglec-8+EOs cells. M, Percent CD45+ cells that are Siglec-8+ mast cells (MCs), eosinophils (EOs), or basophils (Baso). Horizontal bars represent mean percent. ***P < .001 (Mann Whitney). Blood: N = 7 for NSG-BLT and N = 9 for NSG-SGM3 BLT. PECs: N = 7 for NSG-BLT and N = 10 for NSG-SGM3 BLT. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 2 Representative images of tissues of NSG-SGM3 BLT mice stained for human tryptase. A, Human tryptase-positive cells (brown) in NSG-BLT and NSG-SGM3 BLT mice. B, Mast cells by pinacyanol erythrosinate and tryptase staining. C, PECs cultured for 32 days were >90% mast cells by CD117 and FcεRI expression and were stained with human tryptase antibody. Data are representative of PECs from pooled cohorts evaluated in 2 independent experiments. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 3 Phenotype of human CD117+ cells in the peritoneal exudate of NSG-SGM3 BLT mice. Peritoneal cells pooled from 4 NSG-SGM3 BLT mice were recovered and labeled with CD117 (left histogram) and human-specific antibodies of the indicated surface receptors. Representative overlay plots are shown for cells gated on CD117+ population (middle column). Scatter graphs of mean fluorescence intensity, a measure of mean expression level of each cell surface receptor, are plotted (right column). SSC, Side scatter. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 4 Culture of human mast cells from the peritoneal cavity of NSG-SGM3 BLT mice. A, PECs from NSG-SGM3 BLT mice cultured for 16 hours in the presence of human cytokines (100 ng/mL). The percentage of mast cells (gated on FcεRI, >70% of total cells) with surface Annexin-V binding was quantified. Cytokines that supported mast cell survival (*P < .05). B, Representative experiments cultured in the presence of SCF for up to 21 days (3 independent experiments, N = 11, 5, 5). Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 5 NSG-SGM3 BLT PECs bind human IgE, and degranulate in an IgE-dependent and -independent manner. Histograms of sensitized NSG-SGM3 BLT PEC cultures (>90% mast cells) (A) incubated with NP-BSA or Iono (B). C, Calcium flux of panel A cells. D, MFI replicates of panel C. E, NSG-SGM3 BLT PEC mast cell day 34 cultures (20,000 mast cells/well) treated with ionomycin (2 μM) or varying concentrations of Substance P, C3a, C5a. F, Percentage of CD107a cells. Iono, Ionomycin, representative of 2 independent experiments; MFI, mean fluorescence intensity; NP, NP-BSA; pre, baseline values. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 6 NSG-SGM3 BLT mice exhibit pronounced PCA upon antigen challenge. NSG-BLT and NSG-SGM3 BLT were sensitized intradermally with human chIgE-anti-NP and 24 hours later injected intravenously with NP-BSA as described in the Methods section. The ear thickness of the ears was determined at 1 and 24 hours after challenge. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig 7 NSG-SGM3 BLT mice exhibit pronounced PSA upon antigen challenge. NSG-SGM3 BLT mice were sensitized by intravenous injection of chimeric human IgE anti-NP antibody and challenged 24 hours later by intravenous injection of NP-BSA in PBS. Systemic anaphylaxis was measured by monitoring rectal body temperature (A) and by observable symptom scores (B), as described in the Methods section. Journal of Allergy and Clinical Immunology  , DOI: ( /j.jaci ) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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