Effects of nasal corticosteroids on boosts of systemic allergen-specific IgE production induced by nasal allergen exposure

Cornelia Egger, Christian Lupinek, Robin Ristl, Patrick Lemell, Friedrich Horak, Petra Zieglmayer, Susanne Spitzauer, Rudolf Valenta, Verena Niederberger, Cornelia Egger, Christian Lupinek, Robin Ristl, Patrick Lemell, Friedrich Horak, Petra Zieglmayer, Susanne Spitzauer, Rudolf Valenta, Verena Niederberger

Abstract

Background: Allergen exposure via the respiratory tract and in particular via the nasal mucosa boosts systemic allergen-specific IgE production. Intranasal corticosteroids (INCS) represent a first line treatment of allergic rhinitis but their effects on this boost of allergen-specific IgE production are unclear.

Aim: Here we aimed to determine in a double-blind, placebo-controlled study whether therapeutic doses of an INCS preparation, i.e., nasal fluticasone propionate, have effects on boosts of allergen-specific IgE following nasal allergen exposure.

Methods: Subjects (n = 48) suffering from grass and birch pollen allergy were treated with daily fluticasone propionate or placebo nasal spray for four weeks. After two weeks of treatment, subjects underwent nasal provocation with either birch pollen allergen Bet v 1 or grass pollen allergen Phl p 5. Bet v 1 and Phl p 5-specific IgE, IgG1-4, IgM and IgA levels were measured in serum samples obtained at the time of provocation and one, two, four, six and eight weeks thereafter.

Results: Nasal allergen provocation induced a median increase to 141.1% of serum IgE levels to allergens used for provocation but not to control allergens 4 weeks after provocation. There were no significant differences regarding the boosts of allergen-specific IgE between INCS- and placebo-treated subjects.

Conclusion: In conclusion, the application of fluticasone propionate had no significant effects on the boosts of systemic allergen-specific IgE production following nasal allergen exposure.

Trial registration: https://ichgcp.net/clinical-trials-registry/NCT00755066.

Conflict of interest statement

Competing Interests: This study was supported by the Christian Doppler Research Association, Vienna, Austria, and by the following research grants from commercial funders: Biomay, Vienna, Austria, and Thermofisher/Phadia, Uppsala, Sweden. Trial Medication was provided by GlaxoSmithKline. Friedrich Horak has received funding from GSK and collaborated with them on a conduct clinical trial: "A Randomized, Double-blind, Placebo Controlled, Incomplete Block, 3 Way Cross Over Study in Subjects With Allergic Rhinitis to Assess the Effect of Intranasal Repeat Doses of SB-705498 When Administered Alone or in Conjunction With Intranasal Fluticasone Propionate on the Symptoms of Rhinitis in the Vienna Allergen Challenge Chamber." Verena Niederberger has received research grants from the Austrian Science Fund (FWF), Allergy Therapeutics, UK, and Biomay, Vienna, Austria, has received honoraria for speaking at meetings from Thermofisher and has consulted Biomay, Vienna, Austria. Christian Lupinek has received honoraria from Thermofisher. Friedrich Horak has received research grants from Allergy Therapeutics, Calistoga, GSK, Meiji Seika, MSD, Oxagen, Schering Plough, and Stallergenes. Rudolf Valenta has received research grants from the Austrian Science Fund (FWF), from Biomay AG, Vienna, and Thermofisher, Uppsala, Sweden. He serves as a consultant for Biomay AG, Vienna, Austria, and Thermofisher, Uppsala, Sweden. All other authors have no conflicts of interest to declare. There are no further patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Distribution of study subjects.
Fig 1. Distribution of study subjects.
Of the 48 volunteers who were randomized, 45 completed the trial. Drop-outs are marked in yellow. INCS: intranasal corticosteroid; NPT: nasal provocation test; URTI: upper respiratory tract infection; i.m.: intra-muscular
Fig 2. Study design.
Fig 2. Study design.
Patients administered nasal spray containing either nasal fluticasone propionate or placebo (black arrows) for 2 weeks before and after nasal allergen provocation (NP) performed on two consecutive days. Blood samples for measurement of allergen-specific antibodies (white arrows) were obtained at the time of the first nasal provocation (day 1 = t1) and on days 8 (t2), 15 (t3), 29 (t4), 43 (t5) and 57 (t6).
Fig 3. Development of allergen-specific IgE levels.
Fig 3. Development of allergen-specific IgE levels.
Relative changes of IgE-levels (y-axes) to Phl p 5, Bet v 1 and Phl p 1 (top to bottom: right labels of each chart) compared to t1 (day 1) are shown for all visits (t2: day 8; t3: day 15; t4: day 29; t5: day 43; t6: day 57, x-axes). Results for the steroid-treated group are shown in blue, the placebo-group in green. Results from participants challenged with Phl p 5 are depicted in the left column, those for the Bet v 1-challenged group on the right side. Outliers that lie between 1.5 and 3 times the interquartile range below the first or above the third quartile are shown as open circles (“o”), those that lie beyond 3 times the interquartile range are depicted by asterisks (“*”).There were no significant differences between the fluticasone and placebo groups at any time point.
Fig 4. Development of Phl p 5-specific…
Fig 4. Development of Phl p 5-specific antibody responses.
Percentage changes of Phl p 5-specific IgG1, IgG2, IgG4, IgA and IgM antibody levels (y-axes) at the day of the first nasal provocation (0) and thereafter (x-axes). Uninterrupted lines: Patients with steroid spray; dotted lines: Patients with placebo spray; black squares: provocation with rPhl p 5; grey dots: provocation with rBet v 1.
Fig 5. Development of Bet v 1-specific…
Fig 5. Development of Bet v 1-specific antibody responses.
Percentage changes of Bet v 1-specific IgG1, IgG2, IgG4, IgA and IgM antibody levels (y-axes) at the day of the first nasal provocation (0) and thereafter (x-axes). Uninterrupted lines: Patients with steroid spray; dotted lines: Patients with placebo spray; black squares: provocation with rPhl p 5; grey dots: provocation with rBet v 1.

References

    1. Bischoff SC (2007) Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data. Nat Rev Immunol 7: 93–104.
    1. van Neerven RJ, Knol EF, Ejrnaes A, Würtzen PA (2006) IgE-mediated allergen presentation and blocking antibodies: regulation of T-cell activation in allergy. Int Arch Allergy Immunol 141: 119–129.
    1. Bieber T (1997) FcεRI-expressing antigen-presenting cells: new players in the atopic game. Immunol Today 18: 311–313.
    1. Kawakami T, Galli SJ (2002) Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2: 773–786.
    1. Saini SS, MacGlashan D (2002) How IgE upregulates the allergic response. Curr Opin Immunol 14: 694–697.
    1. Gieras A, Focke-Tejkl M, Ball T, Verdino P, Hartl A, et al. (2007) Molecular determinants of allergen-induced effector cell degranulation. J Allergy Clin Immunol 119: 384–390.
    1. Skov-Stahl P, Norh S, Weeke B (1977) Basophil histamine release in patients with hay fever. Results compared with specific IgE and total IgE during immunotherapy. Clin Exp Immunol 27: 432–439.
    1. Fennerty AG, Jones KP, Fifield R, Davies BH (1987) Challenge tests and specific IgE in hay fever sufferers. Clin Allergy 17: 365–372.
    1. Southam DS, Ellis R, Wattie J, Inman MD (2007) Components of airway hyperresponsiveness and their associations with inflammation and remodelling in mice. J Allergy Clin Immunol 119: 848–854.
    1. Dente FL, Bacci E, Di Franco A, Giannini D, Vagaggini B, et al. (2000) Natural exposure to pollen reduces the threshold but does not change the pattern of response to the allergen in allergic subjects. Respir Med 94: 1073–1078.
    1. Niederberger V, Ring J, Rakoski J, Jäger S, Spitzauer S, et al. (2007) Antigens Drive Memory IgE Responses in Human Allergy via the Nasal Mucosa. Int Arch Allergy Immunol 142: 133–144.
    1. Skamstrup Hansen K, Vieths S, Vestergaard H, Skov PS, Bindslev-Jensen C, et al. (2001) Seasonal variation in food allergy to apples. J Chromatogr B Biomed Sci Appl 756: 19–32.
    1. Peroni DG, Boner AL, Vallone G, Antolini I, Warner JO (1994) Effective allergen avoidance at high altitude reduces allergen-induced bronchial hyperresponsiveness. Am J Respir Crit Care Med 149: 1442–1446.
    1. Henderson LL, Larson JB, Gleich GJ (1975) Maximal rise in IgE antibody following ragweed pollination season. J Allergy Clin Immunol 55: 10–15.
    1. Naclerio RM, Adkinson NF Jr, Moylan B, Baroody FM, Proud D, et al. (1997) Nasal provocation with allergen induces a secondary serum IgE antibody response. J Allergy Clin Immunol 100: 505–510.
    1. Mothes N, Heinzkill M, Drachenberg KJ, Sperr WR, Krauth MT, et al. (2003) Allergen-specific immunotherapy with a monophosphoryl lipid A-adjuvanted vaccine: reduced seasonally boosted immunoglobulin E production and inhibition of basophil histamine release by therapy-induced blocking antibodies. Clin Exp Allergy 33: 1198–1208.
    1. Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, et al. (2004) Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A 101 Suppl 2: 14677–14682
    1. Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, et al. (2006) Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 355:1445–1455
    1. Gadermaier E, Staikuniene J, Scheiblhofer S, Thalhamer J, Kundi M (2011) Recombinant allergen-based monitoring of antibody responses during injection grass pollen immunotherapy and after 5 years of discontinuation. Allergy 66:1174–1182 10.1111/j.1398-9995.2011.02592.x
    1. Hemady Z, Gellis S, Chambers M, Rocklin RE (1985) Effect of dexamethasone on de novo IgE synthesis by human blood lymphocytes. J Allergy Clin Immunol 75: 304–312.
    1. Fischer A, König W (1990) Regulation of CD23 expression, soluble CD23 release and immunoglobulin synthesis of peripheral blood lymphocytes by glucocorticoids. Immunology 71: 473–479.
    1. Bohle B, Willheim M, Baier K, Stadler B, Spitzauer S, et al. (1995) Hydrocortisone enhances total IgE levels—but not the synthesis of allergen- specific IgE—in a monocyte-dependent manner. Clin Exp Immunol 101: 474–479.
    1. Cho YJ, Hong SJ, Moon HB (2000) Hydrocortisone enhances allergen-specific IgE production by peripheral blood mononuclear cells from atopic patients with high serum allergen-specific IgE levels. Clin Exp Allergy 30: 1576–1581.
    1. Zieg G, Lack G, Harbeck RJ, Gelfand EW, Leung DY (1994) In vivo effects of glucocorticoids on IgE production. J Allergy Clin Immunol 94: 222–230.
    1. Durham SR, Gould HJ, Thienes CP, Jacobson MR, Masuyama K, et al. (1997) Expression of epsilon germ-line gene transcripts and mRNA for the epsilon heavy chain of IgE in nasal B cells and the effects of topical corticosteroid. Eur J Immunol 27: 2899–2906.
    1. Henderson LL, Larson JB, Gleich GJ (1973) Effect of corticosteroids on seasonal increases in IgE antibody. J Allergy Clin Immunol 52: 352
    1. Naclerio RM, Adkinson NF Jr, Creticos PS, Baroody FM, Hamilton RG, et al. (1993) Intranasal steroids inhibit seasonal increases in ragweed-specific immunoglobulin E antibodies. J Allergy Clin Immunol 92: 717–721.
    1. Pullerits T, Praks L, Sjöstrand M, Rak S, Skoogh BE, et al. (1997) An intranasal glucocorticoid inhibits the increase of specific IgE initiated during birch pollen season. J Allergy Clin Immunol 100: 601–605.
    1. Laffer S, Valenta R, Vrtala S, Susani M, van Ree R, et al. (1994) Complementary DNA cloning of the major allergen Phl p I from timothy grass (Phleum pratense); recombinant Phl p I inhibits IgE binding ot group I allergens from eight different grass species. J Allergy Clin Immunol 94: 689–698.
    1. Vrtala S, Sperr WR, Reimitzer I, van Ree R, Laffer S, et al. (1993) cDNA cloning of a major allergen from timothy grass (Phleum pratense) pollen; characterization of the recombinant Phl p V allergen. J Immunol 151: 4773–4781.
    1. Breiteneder H, Pettenburger K, Bito A, Valenta R, Kraft D, et al. (1989) The gene coding for the major birch pollen allergen Bet v 1, is highly homologous to a pea disease resistance response gene. EMBO J 8: 1935–1938.
    1. Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F (1999) Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 341: 468–75.
    1. Egger C, Horak F, Vrtala S, Valenta R, Niederberger V (2010) Nasal application of rBet v 1 or no-IgE-reactive T-cell epitope-containing rBet v 1 fragments has different effects on systemic allergen-specific antibody responses. J Allergy Clin Immunol 126:1312–1315. 10.1016/j.jaci.2010.06.008
    1. Schäppi GF, Taylor PE, Pain MC, Cameron PA, Dent AW, et al. (1999) Concentrations of major grass group 5 allergens in pollen grains and atmospheric particles: implications for hay fever and allergic asthma sufferers sensitized to grass pollen allergens. Clin Exp Allergy 29: 633–641.
    1. Andersson K, Lidholm J (2003) Characteristics and immunobiology of grass pollen allergens. Int Arch Allergy Immunol 130: 87–107.
    1. Mösges R, Lehmacher W, Pasch N, Vent J (2009) Assessment of the antiobstructive effect of fexofenadine on nasal allergy challenge in patients with seasonal allergic rhinitis. Asian Pac J Allergy Immunol 27:181–90.
    1. Hanf G, Noga O, O'Connor A, Kunkel G (2004) Omalizumab inhibits allergen challenge-induced nasal response. Eur Respir J 23:414–8.
    1. Kawakami T, Galli SJ (2002) Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immmunol 2: 773–786.
    1. Möller C, Dreborg S, Ferdousi HA, Halken S, Høst A, et al. (2002) Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 109: 251–256
    1. Durham SR, Walker SM, Varga EM, Jacobson MR, O'Brien F, et al. (1999) Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 341: 468–475
    1. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, et al. (2008) Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy 63 Suppl 86:8–160. 10.1111/j.1398-9995.2007.01620.x
    1. Fokkens W, Lund V, Bachert C, Clement P, Hellings P, et al. (2005) EAACI Position Paper on Rhinosinusits and Nasal Polyps Executive Summary. Allergy 60: 583–601.
    1. Passalacqua G, Albano M, Canonica GW, Bachert C, Van Cauwenberge P, et al. (2000) Inhaled and nasal corticosteroids: safety aspects. Allergy 55:16–33.
    1. Agertoft L, Pedersen S (1994) Effects of long-term treatment with an inhaled corticosteroid on growth and pulmonary function in asthmatic children. Respir Med 88: 373
    1. Haahtela T, Jarvinen M, Kava T, Kiviranta K, Koskinen S, et al. (1994) Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med 331: 700
    1. Selroos O, Pietinalho A, Lofroos AB, Riska H (1995) Effect of early vs late intervention with inhaled corticosteoids in asthma. Chest 108: 1228
    1. Ferreira FD, Mayer P, Sperr WR, Valent P, Seiberler S, et al. (1996) Induction of IgE antibodies with predefined specificity in rhesus monkeys with recombinant birch pollen allergens, Bet v 1 and Bet v 2. J Allergy Clin Immunol 97: 95–103.
    1. Durham SR, Gould HJ, Hamid QA (1997) Local IgE production in nasal allergy. Int Arch Allergy Immunol 113: 128–130
    1. Vrtala S, Ball T, Spitzauer S, Pandjaitan B, Suphioglu C, et al. (1998) Immunization with purified natural and recombinant allergens induces mouse IgG1 antibodies that recognize similar epitopes as human IgE and inhibit the human IgE-allergen interaction and allergen-induced basophil degranulation. J Immunol 15: 6137–6144.
    1. Derendof H, Meltzer EO (2008) Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy 63: 1292–1300. 10.1111/j.1398-9995.2008.01750.x
    1. Rak S, Jacobson MR, Sudderick RM, Masuyama K, Juliusson S, et al. (2006) Influence of prolonged treatment with topical corticosteroid (fluticasone propionate) on early and late phase nasal responses and cellular infiltration in the nasal mucosa after allergen challenge. Clin Exp Allergy 24:930–939.

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