Ellen Mueller Fox, PhD, Marina N

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Presentation transcript:

Immunologic characterization of 3 murine regimens of allergen-specific immunotherapy Ellen Mueller Fox, PhD, Marina N. Torrero, PhD, Holly Evans, BS, Edward Mitre, MD Journal of Allergy and Clinical Immunology Volume 135, Issue 5, Pages 1341-1351.e7 (May 2015) DOI: 10.1016/j.jaci.2014.07.052 Copyright © 2014 Terms and Conditions

Fig 1 Sensitization with alum-OVA results in increased circulating IgE levels and basophil activation in response to OVA. A, Total circulating IgE levels, as determined by using ELISA. B, Circulating OVA-specific IgE levels, as determined by using ELISA. C, Gating strategy to identify activated basophil populations. D, Basophil activation in control and OVA-sensitized mice in response to medium and OVA stimulation. Data are from 2 combined independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .001. n.s., Not significant. Differences between 2 unpaired groups were tested for significance by using the 1-tailed Mann-Whitney test. APC, Allophycocyanin; FITC, fluorescein isothiocyanate; FSC, forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 2 Sensitization to alum-OVA results in increased IL-4 and IL-5 production. A-C, IL-4, IL-5, and IFN-γ production by splenocytes after anti-CD3/anti-CD28 activation, as determined by means of ELISA. D-F, IL-4, IL-5, and IFN-γ production by splenocytes after OVA activation, as determined by means of ELISA. Data are from 2 combined independent experiments. *P < .05, ***P < .001, and ****P < .001. n.s., Not significant. Differences between 2 unpaired groups were tested for significance by using the 1-tailed Mann-Whitney test. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 3 Sensitization with alum-OVA results in increased local anaphylaxis. A, Example of local anaphylaxis and dye extravasation in mouse ears. OVA (left) and PBS (right) challenges are shown. B, Local anaphylaxis in control and OVA-sensitized mice, as determined by using the local anaphylaxis assay. Data are from 2 combined independent experiments. ***P < .001. n.s., Not significant. Differences between 2 paired groups were determined by using Wilcoxon matched-pairs signed rank test. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 4 Repeated treatment with OVA results in decreased local anaphylaxis in response to antigen challenge. OVA-sensitized mice treated with desensitization protocols have decreased local anaphylaxis in response to local antigen challenge. Data are combined from 2 independent experiments. ***P < .001. ns, Not significant. Differences between 2 paired groups were determined by using Wilcoxon matched-pairs signed rank test. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 5 Desensitization with OVA results in changes in circulating OVA-specific IgE, IgG1, and IgG2a levels. A, Circulating OVA-specific IgE levels, as determined by using ELISA. B, Circulating OVA-specific IgG1 levels, as determined by using ELISA. C, Circulating OVA-specific IgG2a levels, as determined by using ELISA. Data are combined from 2 independent experiments. **P < .01, ***P < .001, and ****P < .001. n.s., Not significant. Differences between multiple groups were tested by using the Kruskal-Wallis test, followed by Dunn multiple comparison tests. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 6 Desensitization with OVA results in changes in splenocyte cytokine production. A-C, IL-4, IL-5, and IFN-γ production by splenocytes stimulated with anti-CD3/anti-CD28, as determined by using ELISA. D-F, IL-4, IL-5, and IFN-γ production by splenocytes stimulated with OVA, as determined by using ELISA. Data are combined from 2 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .001. n.s., Not significant. Differences between multiple groups were tested by using the Kruskal-Wallis test, followed by Dunn multiple comparison tests. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 7 Moderate and intermediate desensitization results in increased IL-10 production and Treg cell numbers and decreased proliferation. A and B, IL-10 production in splenocytes after anti-CD3/anti-CD28 (Fig 7, A) and OVA stimulation (Fig 7, B), as determined by using ELISA. C, Total number of splenic CD4+CD25+Foxp3+ T cells in control and desensitized mice determined by using flow cytometry. D and E, Splenocyte proliferation in response to anti-CD3/anti-CD28 (Fig 7, D) and OVA (Fig 7, E) stimulation, as determined by using BrdU incorporation. PI, Proliferation index. Data are combined from 2 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .001. n.s., Not significant. Differences between multiple groups were tested by using the Kruskal-Wallis test, followed by Dunn multiple comparison tests. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig 8 OVA desensitization results in decreased basophil activation. Basophil activation from whole blood in response to OVA (2 and 20 μg) stimulation, as determined by means of flow cytometry. A-C, Rapid (Fig 8, A), intermediate (Fig 8, B), and gradual (Fig 8, C) protocols. D-F, Basophil activation from whole blood in response to anti-IgE (various concentrations) stimulation determined by means of flow cytometry: rapid (Fig 8, D), moderate (Fig 8, E), and gradual (Fig 8, F) protocols. Data are combined from 2 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .001. n.s., Not significant. Differences between multiple groups were tested by using the Kruskal-Wallis test, followed by Dunn Multiple comparison tests. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E1 Desensitization protocols used in this study. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E2 Mast cells and histamine are required for local anaphylaxis. Local sensitivity to OVA challenge, as determined by using a local anaphylaxis assay, is shown. PBS ear (data not shown) absorbance was subtracted. Data are from 2 combined independent experiments. HR1/HR2, Antihistamine treated OVA-sensitized mice; Ba103, basophil depleted OVA-sensitized mice; ns, not significant; Wsh-/-, mast cell deficient mice. ***P < .001. Differences between multiple groups were tested by using the Kruskal-Wallis test, followed by Dunn multiple comparison tests. Differences between 2 unpaired groups were tested for significance by using the 1-tailed Mann-Whitney test. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E3 Gating strategy to identify Treg cells. APC, Allophycocyanin; FITC, fluorescein isothiocyanate; FSC, forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E4 Desensitization of mice with a rapid-build approach results in decreased local anaphylaxis in response to antigen challenge. OVA-sensitized mice treated with desensitization protocols result in decreased local anaphylaxis in response to local antigen challenge. ****P < .0001. Differences between 2 paired groups were determined by using Wilcoxon matched-pairs signed rank test. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E5 Rapid and rapid-build administration of OVA does not result in changes in rectal temperature. Rectal temperatures of OVA-sensitized mice were assessed after intraperitoneal OVA administration. Differences between 2 unpaired groups were tested for significance by using the Mann-Whitney test. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E6 Repeated injection of OVA does not increase allergic activity. Mice were observed for 30 minutes after antigen injection and assessed for changes in nose scratching (A), injection site scratching (B), and movement (C). 0, No change in baseline behavior; 1, mild change in baseline behavior; 2, moderate change in baseline behavior; and 3, excessive/uncontrollable change in behavior. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions

Fig E7 Summary of clinical and immunologic changes after desensitization by using our rapid, intermediate, and gradual regimens. –, No change. Journal of Allergy and Clinical Immunology 2015 135, 1341-1351.e7DOI: (10.1016/j.jaci.2014.07.052) Copyright © 2014 Terms and Conditions