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No impact of filaggrin deficiency on the efficacy of epicutaneous immunotherapy in a murine model

1 DBV Technologies, Montrouge, France
2 Université Paris Descartes-Hôpital Necker-Enfants Malades, Paris, France

Background: Epicutaneous immunotherapy (EPIT®), currently investigated in the treatment of food allergy, needs the integrity of the skin to warrant safety and efficacy. Mutations in the gene encoding the key epidermal protein filaggrin (FLG) are risk factors for peanut allergy and disrupt the skin intergrity. We investigated the association between FLG deficiency and peanut EPIT® efficacy in a murine model. Methods: FLG mutant mice deficient in filaggrin (FLG-/-) or wild-type (WT) mice were sensitized with peanut protein extract (peanut protein) and cholera toxin. Sensitized mice received a patch per week during 8 weeks for EPIT®, using Viaskin®, and were then submitted to sustained peanut oral exposure. We assessed blood humoral and cellular responses and evaluated eosinophil infiltration in the gut mucosa. The different steps of allergen capture and transportation following deposition on the skin was also analyzed in sensitized mice. Results: Sensitization of mice was confirmed by a significant increase of specific Th2 biaised immunological responses. In sensitized mice, EPIT® significantly reduced IgE levels, splenocytes secretion of Th2 cytokines and recruitment of eosinophils in esophagus, compared to sensitized mice without epicutaneous immunotherapy. The allergen applied onto the skin of FLG-/- mice did not undergo passive skin passage or systemic delivery. Instead, the allergen was captured by skin CD205high DCs, which migrated to afferent lymph nodes, as already described in WT mice. Conclusions: EPIT® was efficient and safe in FLG-/- mice, suggesting that in Humans EPIT® keeps efficacy and safety in the presence of loss of function of FLG.
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1. Irvine AD, McLean WH, Leung DY (2011) Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 365: 1315–1327.    

2. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. (2006) Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 38: 441–446.    

3. Brown SJ, Asai Y, Cordell HJ, et al. (2011) Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J Allergy Clin Immunol 127: 661–667.    

4. Marenholz I, Nickel R, Ruschendorf F, et al. (2006) Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 118: 866–871.    

5. Weidinger S, Rodriguez E, Stahl C, et al. (2007) Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol 127: 724–726.    

6. Kawasaki H, Nagao K, Kubo A, et al. (2012) Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol 129: 1538–1546.

7. Dupont C, Kalach N, Soulaines P, et al (2010) Cow's milk epicutaneous immunotherapy in children: a pilot trial of safety, acceptability, and impact on allergic reactivity. J Allergy Clin Immunol 125: 1165–1167.    

8. Mondoulet L, Dioszeghy V, Larcher T, et al. (2012) Epicutaneous immunotherapy (EPIT) blocks the allergic esophago-gastro-enteropathy induced by sustained oral exposure to peanuts in sensitized mice. PLoS One 7: e31967.    

9. Dioszeghy V, Mondoulet L, Dhelft V, et al. (2011) Epicutaneous immunotherapy results in rapid allergen uptake by dendritic cells through intact sSkin and downregulates the allergen-specific response in sensitized mice. J Immunol 186: 5629–5637.

10. Mondoulet L, Dioszeghy V, Ligouis M, et al. (2010) Epicutaneous immunotherapy on intact skin using a new delivery system in a murine model of allergy. Clin Exp Allergy 40: 659–667.

11. Mondoulet L, Dioszeghy V, Vanoirbeek J, et al. (2011) Epicutaneous immunotherapy using a new epicutaneous delivery system in mice sensitized to peanut. Int Arch Allergy Immunol 154: 299–309.    

12. Mondoulet L, Dioszeghy V, Puteaux E, et al. (2012) Intact skin and not stripped skin is crucial for the safety and efficacy of peanut epicutaneous immunotherapy (EPIT) in mice. Clin Transl Allergy 2: 22–34.

13. Jones SM, Agbotounou WK, Fleischer DM, et al. (2016) Safety of epicutaneous immunotherapy for the treatment of peanut allergy: A phase 1 study using the Viaskin patch. J Allergy Clin Immunol 137: 1258–1261.

14. Sampson HA, Agbotounou W, Thebaut C, et al. (2015) Epicutaneous immunotherapy (EPIT) is effective and safe to treat peanut allergy: a multi-national double-blind placebo-controlled randomized phase IIb trial. J Allergy Clin Immunol 135: AB390.

15. Presland RB, Boggess D, Lewis SP, et al. (2000) Loss of normal profilaggrin and filaggrin in flaky tail (ft/ft) mice: an animal model for the filaggrin-deficient skin disease ichthyosis vulgaris. J Invest Dermatol 115: 1072–1081.    

16. Stout TE, McFarland T, Mitchell JC, et al. (2014) Recombinant filaggrin is internalized and processed to correct filaggrin deficiency. J Invest Dermatol 134: 423–429.

17. Fallon PG, Sasaki T, Sandilands A, et al. (2009) A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet 41: 602–608.    

18. Sasaki T, Shiohama A, Kubo A, et al. (2013) A homozygous nonsense mutation in the gene for Tmem79, a component for the lamellar granule secretory system, produces spontaneous eczema in an experimental model of atopic dermatitis. J Allergy Clin Immunol 132: 1111–1120.    

19. McAleer MA, Irvine AD (2013) The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 131: 280–291.    

20. Moniaga CS, Kabashima K (2011) Filaggrin in atopic dermatitis: flaky tail mice as a novel model for developing drug targets in atopic dermatitis. Inflamm Allergy Drug Targets 10: 477–485.    

21. Moniaga CS, Egawa G, Kawasaki H (2010) Flaky tail mouse denotes human atopic dermatitis in the steady state and by topical application with Dermatophagoides pteronyssinus extract. Am J Pathol 176: 2385–2393.    

22. Saunders SP, Goh CS, Brown SJ, et al. (2013) Tmem79/Matt is the matted mouse gene and is a predisposing gene for atopic dermatitis in human subjects. J Allergy Clin Immunol 132: 1121–1129.    

23. Kawasaki H, Nagao K, Kubo A, et al. (2012) Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol 129: 1538–1546.

24. Oyoshi MK, Murphy GF, Geha RS (2009) Filaggrin-deficient mice exhibit TH17-dominated skin inflammation and permissiveness to epicutaneous sensitization with protein antigen. J Allergy Clin Immunol 124: 485–493.

25. Spergel JM, Mizoguchi E, Brewer JP, et al. (1998) Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 101: 1614–1622.    

26. Strid J, Callard R, Strobel S (2006) Epicutaneous immunization converts subsequent and established antigen-specific T helper type 1 (Th1) to Th2-type responses. Immunology 119: 27–35.    

27. Lack G, Fox D, Northstone K, et al. (2003) Factors associated with the development of peanut allergy in childhood. N Engl J Med 348: 977–985.    

Copyright Info: © 2017, Lucie Mondoulet, et al., licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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