Specific epicutaneous immunotherapy prevents sensitization to new allergens in a murine model Lucie Mondoulet, PhD, Vincent Dioszeghy, PhD, Emilie Puteaux,

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Specific epicutaneous immunotherapy prevents sensitization to new allergens in a murine model Lucie Mondoulet, PhD, Vincent Dioszeghy, PhD, Emilie Puteaux, BSc, Mélanie Ligouis, BSc, Véronique Dhelft, BSc, Camille Plaquet, BSc, Christophe Dupont, MD, PhD, Pierre-Henri Benhamou, MD Journal of Allergy and Clinical Immunology Volume 135, Issue 6, Pages 1546-1557.e4 (June 2015) DOI: 10.1016/j.jaci.2014.11.028 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Experimental design and sampling. A, Milk EPIT prevention against PPE sensitization. Mice were sensitized to milk by means of oral gavage with CMP/CT. On day 43, sensitized mice were epicutaneously treated with a Viaskin patch loaded with milk protein extract (EPIT) or a placebo Viaskin patch (sham). On day 99, EPIT- or sham-treated mice were exposed to a protocol of sensitization by means of gavage with PPE/CT, followed on day 127 by sustained oral exposure to peanut for 10 days. Positive control animals were naive mice sensitized to PPE by using the same protocol. Negative control animals were naive mice without sensitization or immunotherapy protocols. B, Milk EPIT prevention against HDM sensitization. Mice were sensitized to milk by means of oral gavage with CMP/CT and then epicutaneously treated with a Viaskin patch loaded with milk protein extract (EPIT) or a placebo Viaskin patch (sham). On day 99, EPIT- or sham-treated mice were exposed to a protocol of sensitization by means of subcutaneous injections of HDM/alum, followed on day 127 by 3 aerosol challenges to HDM. Positive control animals were naive mice sensitized with HDM by using the same protocol. Negative control animals were naive mice without sensitization or immunotherapy protocols. C, HDM EPIT prevention against pollen sensitization. Mice were sensitized to HDM by means of subcutaneous injections with HDM. On day 28, sensitized mice were epicutaneously treated with a Viaskin patch loaded with HDM protein extract (EPIT) or a placebo Viaskin patch (sham). On day 90, EPIT- or sham-treated mice were exposed to a protocol of sensitization by means of subcutaneous injections with pollen/alum, followed on day 117 by 3 days of aerosol to pollen. Positive control animals were naive mice sensitized with pollen extract by using the same protocol. Negative control animals were naive mice without sensitization or immunotherapy protocols. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Experimental design to evaluate the role of Treg cells. Mice were sensitized to milk and then epicutaneously treated with milk (EPIT) or placebo (sham) Viaskin. After 8 weeks of treatment, mice were killed, and Treg cells were isolated from spleen cells of each group (EPIT Treg and sham Treg cells, Phase 1). Two groups of naive mice were adoptively transferred with EPIT Treg or sham Treg cells, followed by PPE sensitization (Phase 2, A and B). Positive control animals were naive mice sensitized to PPE (Phase 2, C, positive control). Negative control animals were naive mice without transfer or sensitization (Phase D, negative control). All of them were exposed to the peanut regimen. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Serologic and cellular responses to peanut sensitization after milk EPIT. A-C, Sera were harvested before (day 99) and after (day 127) PPE sensitization of the positive control, sham, and EPIT groups, respectively, for the measurement of IgE, IgG2a, and IgG1 reactive to PPE. D-H, Measurement of secreted cytokines by reactivated splenocytes. I, The percentage of CD4+CD25+Foxp3+ cells was evaluated among reactivated splenocytes. J, Eosinophilic infiltration into the esophageal mucosa was determined in all groups after a 10-day period of exposure to peanuts and expressed as mean ± SD numbers of eosinophils per square millimeter. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Serologic and cellular responses to HDM sensitization after milk EPIT. A-C, Sera were harvested before (day 99) and after (day 127) HDM sensitization of the positive control, sham, and EPIT groups, respectively, for the measurement of IgE, IgG2a, and IgG1 reactive to PPE. D-H, Measurement of secreted cytokines by reactivated splenocytes. I, The percentage of CD4+CD25+Foxp3+ cells was evaluated among reactivated splenocytes. J, AHR was investigated in the negative control, positive control, sham, and EPIT groups after 3 days of aerosol challenges to HDM and exposure to increasing doses of methacholine. The area under the curve (AUC) with individual mice is shown. K, Eosinophilic infiltration was evaluated 48 hours after the last aerosol challenge to HDM in sensitized mice for the negative control, positive control, sham, and EPIT groups. L-O, Hematoxylin and eosin staining of lung sections was analyzed 48 hours after aerosol from the negative control (Fig 4, L), positive control (Fig 4, M), sham (Fig 4, N), and EPIT (Fig 4, O) groups. Values are expressed as means ± SDs. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 EPIT-induced Treg cells prevent PPE sensitization. A, Eosinophil esophageal infiltration was determined in the negative control, positive control, sham Treg, and EPIT Treg groups after a 10-day period of exposure to PPE. Results are expressed as mean ± SD numbers of eosinophils per square millimeter. *P < .05. B, AHR was investigated in the negative control, positive control, sham Treg, and EPIT Treg groups after 3 days of aerosol challenges to PPE and exposure to increasing doses of methacholine. Values are expressed as the mean ± SD area under the curve (AUC) with individual mice. **P < .01. C, Eosinophilic infiltration was evaluated 48 hours after the last aerosol challenge to peanut in sensitized mice after adoptive transfer of Treg cells generated in milk-sensitized mice treated or not with EPIT. Results are shown for the negative control, positive control, sham Treg, and EPIT Treg groups. Results are expressed as means ± SDs. *P < .05. D and F, Anaphylaxis was evaluated by measuring body temperature 30 minutes after intravenous injection of peanut proteins in the negative control, positive control, sham Treg, and EPIT Treg groups from naive or milk-sensitized recipients, respectively. Individual data are plotted, as are medians *P < .05, **P < .01, and ***P < .001. E and G, mMCP1 as a marker of mast cell degranulation was measured in plasma 30 minutes after intravenous injection of peanut proteins from naive or milk-sensitized recipients, respectively. Individual data are plotted, as are medians. ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 EPIT-induced methylation of the GATA-3 promoter. Methylation levels of transcription factor promoters (GATA-3 and T-bet) were investigated in the negative control, sham, and EPIT groups. A, GATA-3 methylation status immediately after the end of milk EPIT. B, T-bet methylation status just after the end of milk EPIT. C, GATA-3 methylation status after the second period of sensitization to peanut. D, T-bet methylation status after the second period of sensitization to peanut. Values are expressed as means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Humoral response to milk protein during EPIT in milk-sensitized mice. Sera were harvested after sensitization (day 43), after 4 (day 78) or 8 weeks (day 99) of EPIT, and 1 month after EPIT (day 127). A-C, Specific IgE response (Fig E1, A), specific IgG1 response (Fig E1, B), and specific IgG2a response (Fig E1, C) for the negative control, sham, and EPIT groups. Results are expressed as means ± SDs. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Eosinophilic infiltration into the esophageal mucosa was determined in the negative control, positive control, sham, and EPIT groups after a 10-day exposure to peanuts. A, Evaluation of protection 1 month after the end of EPIT. B, Evaluation of protection 2 months after the end of EPIT. Results are expressed as mean ± SD numbers of eosinophils per square millimeter. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Serologic and cellular responses to pollen sensitization after HDM EPIT. A-C, Sera were harvested before (day 99) and after (day 127) pollen sensitization of the positive control, sham, and EPIT groups, respectively, for the measurement of IgE, IgG2a, and IgG1 reactive to PPE. D, AHR was investigated in the negative control, positive control, sham, and EPIT groups after 3 days of aerosol challenges to pollen and exposure to increasing doses of methacholine. Values are expressed as the mean ± SD area under the curve (AUC) with individual mice. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Cytokine (IL-4, IL-5, and IL-13) secretions in the negative control, positive control, sham Treg, and EPIT Treg groups after 3 days of in vitro stimulation with milk or PPE. Values are expressed as means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2015 135, 1546-1557.e4DOI: (10.1016/j.jaci.2014.11.028) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions