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Polydesensitisation with reducing elevated serum total IgE by IFN-gamma therapy in atopic dermatitis: IFN-gamma and polydesensitisation (PDS)
Cytokine 64 (2013) 395–403
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Polydesensitisation with reducing elevated serum total IgE by IFN-gamma therapy in atopic dermatitis: IFN-gamma and polydesensitisation (PDS) Jae Ho Lee a, Geunwoong Noh b,c,⇑ a b c
Department of Paediatrics, Chungnam National University, Dajeon, Republic of Korea Department of Paediatrics & International Allergy Centre, Pyeongtaek International Hospital, Pyeongtaek, Republic of Korea Seoul Allergy Clinic, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 27 November 2012 Received in revised form 21 March 2013 Accepted 17 May 2013 Available online 17 June 2013 Keywords: IFN-gamma Polydesensitisation Serum total IgE Atopic dermatitis
a b s t r a c t Background: AD patients exhibit sensitisation to multiple allergens due to a Th1/Th2 imbalance. Until now, it was impossible to improve the polysensitised status and elevated serum total IgE levels. In this study, the effects of IFN-gamma on systemic polysensitisation to multiple allergens and on serum total IgE levels are investigated. Methods: A total of 44 AD patients whose food allergies were completely controlled and who were polysensitised to multiple allergens according to the SPT were selected. Twenty-two of these patients received IFN-gamma therapy twice a week for 2 months, and 22 patients did not receive this therapy. The blood eosinophil % and serum total IgE levels were assessed, and a skin prick test for 51 allergens was performed before and after the IFN-gamma therapy. Results: With IFN-gamma therapy, the polysensitisation status was improved, as demonstrated by a decrease in the positive allergen count and skin reactivity (systemic polydesensitisation). The improvement in the polysensitised status was accompanied by a decrease in serum total IgE levels. The change in serum total IgE levels was significantly correlated with the change in polysensitisation status. Conclusions: IFN-gamma therapy resulted in systemic polydesensitisation with reduced levels of serum total IgE. IFN-gamma is indicated in AD patients with high serum total IgE levels whose food allergies are well controlled and who are polysensitised to multiple allergens. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Atopic dermatitis is a chronic relapsing allergic skin disease that is characterised by advanced eczematous skin lesions. The basic immunopathogenesis associated with the development of atopic dermatitis is a Th1/Th2 imbalance with consequent allergy sensitisation and the acquisition of an allergy to a specific allergen, including a food allergen and/or aeroallergen [1]. As a result of an allergenic sensitisation, the skin prick test and allergen-specific IgE levels become positive [2,3]. IFN-gamma is a Th1 cytokine and is known to have anti-allergic properties [1]. During the process of antigen sensitisation, IFNAbbreviations: PDS, polydesensitisation; IFN-c, interferon-gamma; SPT, skin prick test; AD, atopic dermatitis; Dp, dermatophagoides pteronyssinus; Df, dermatophagoides farinae. ⇑ Corresponding author. Address: Department of Paediatrics and International Allergy Centre, Pyeongtaek International Hospital, 109 Bangchuk-gil, Godeokmyeon, Pyeongtaek, Gyeonggi Province 451-841, Republic of Korea. Tel.: +82 2 540 4923; fax: +82 2 511 2667. E-mail address: [email protected] (G. Noh). 1043-4666/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2013.05.011
gamma leads to Th1 immune responses, and Th2 cytokines, including IL-4 and IL-5, lead to Th2 immune responses. Allergen-specific immunotherapy with IFN-gamma has been shown to have tolerogenic effects for certain allergens, including house dust mites and food allergens [4–6]. In this study, we investigated the effects of systemic administration of IFN-gamma on the desensitisation of multiple allergens without the introduction of specific allergens. A new concept of polydesensitisation (PDS) is suggested. 2. Patients and methods 2.1. Subjects and study design The study subjects consisted of 44 patients who visited the Department of Allergy and Clinical Immunology at the Seoul Allergy Clinic (Seoul, Korea) and met the Hanifin and Rajka criteria [7]. The mean patient age was 19.6 ± 12.7 years (M:F = 23:21) (Fig. 1). The patients’ food allergies had been controlled for at least 6 months, as described in the previous report [6], and they were polysensitised to multiple allergens, as demonstrated by the SPT.
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Fig. 1. Study design. Patients whose food allergies were completely controlled and who were polysensitised to multiple allergens, as evidenced by high serum total IgE levels, were selected. Laboratory tests used to determine clinical severity scores were performed before and after IFN-gamma therapy.
Polysensitisation was defined in the previous report as sensitivity to three or more allergens [8]. Among the 44 subjects, 22 patients (mean age = 18.2 ± 9.4 years, M:F = 11:11) received IFN-gamma therapy as scheduled, and the 22 patients (mean age = 20.8 ± 14.3 years, M:F = 12:10) in the control group were untreated. All subjects received a blood test and skin prick test (SPT) before and after the IFN-gamma therapy. The tests included complete blood counts and an assessment of differential serum total IgE, serum eosinophil cationic protein (ECP) and IgE levels for specific allergens. A SPT was performed for 50 allergens, including pollens, fungi, danders, Dp/Df and food allergens. The clinical severity was evaluated before and after the intervention using the SCORing Atopic Dermatitis (SCORAD) index, which is used worldwide to assess the severity of atopic eczema [9]. The subjects or their parents signed consent forms that included information concerning this study, especially information regarding the possibility of an emergency situation due to acute anaphylactic reactions to the oral challenge tests. The study was approved by the Ethics Committee of Chungnam National University Hospital, Daejeon, Korea. 2.2. Blood tests and SPT Blood testing on each patient included a CBC with differential counts for the eosinophil fraction, serum total IgE levels, and spe-
cific IgE for milk, eggs, soybeans, wheat, Dp and Df. These tests were conducted before and after the tolerance induction. Foodspecific IgE levels were measured using the UniCapÒ (Pharmacia & Upjohn Diagnostics AB, Uppsala, Sweden) method. The SPTs were conducted on the patients’ left forearms using commercial allergen extracts (Bencard, Brentford, England). Histamine hydrochloride (1 mg/ml) (Bencard) was used as a positive control. Physiologic saline, distilled water, and glycerol were used as negative controls. A minimum wheal size of 3 mm was used to indicate a positive reaction to histamine, and the ratios of the wheal sizes resulting from the allergens to the wheal size resulting from histamine were calculated.
2.3. IFN-gamma therapy Patients received an IFN-c injection three times a week for 8 weeks. Recombinant IFN-c (Intermax gamma, LGCI, Seoul, Korea), with a specific activity of 2 106 IU (50 mg), was administered by subcutaneous injection at a dose of 3 106 IU/m2 according to the body surface area, as previously reported [10]. Although the patients were instructed to take oral acetaminophen (10 mg/kg, up to a maximum dose of 600 mg) twice, at 1 h and 4 h after the injection, to reduce the possibility of side effects (e.g., myalgia, fever, or flu-like symptoms), none of the subjects exhibited symptoms or took oral acetaminophen.
2.4. Skin sensitisation profiles Three skin sensitisation profiles were used for the evaluation of the polysensitisation status and polydesensitisation effects of IFNgamma. A positive item count refers to the number of items that yield positive SPT results. The mean skin reactivity is the average of the grade of the skin prick test for all positive allergens. The grade of the skin prick test was calculated by the ratio of the wheal size for allergens to the wheal size for histamine. The skin sensitisation index is the sum of the score of the skin prick test for all positive allergens.
Fig. 2. Clinical and laboratory changes induced by IFN-gamma therapy. (a) Clinical severity scores, (b) WBC counts, (c) blood eosinophil percentages, and (d) serum total IgE levels.
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Table 1 Clinical and laboratory changes induced by IFN-gamma.
⁄
p-value < 0.05.
Fig. 3. Levels of MSR to various allergens and IFN-gamma effects. MSR levels in: (a) total patients before the intervention, (b) total patients after the intervention, (c) treated patients after the intervention, and (d) control patients after the intervention.
Table 2 Characteristics of MSR to various allergens before and after IFN-gamma therapy.
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Fig. 4. IFN-gamma effects on skin sensitisation profiles. (a) Positive item counts (PICs) for allergen groups, (b) mean skin reactivity (MSR) to allergen groups, and (c) skin sensitisation index (SSI) for allergen groups.
2.5. Statistical analysis The mean and standard deviations were calculated for comparison of the results before and after the intervention using the Wilcoxon signed-rank test and paired t-test to evaluate the effects of the IFN-gamma therapy. The Kruskal–Wallis one-way analysis of variance on ranks was performed to compare the difference of the means of MSR between the allergen groups. A linear regression was performed to analyse the relationship between changes in the skin sensitisation profiles and serum total IgE levels. P-values < 0.05 were considered significant. The statistical analysis
was performed using SigmaPlot software (Systat Software Inc., San Jose, CA, USA).
3. Results 3.1. IFN-gamma effects on clinical severity and laboratory changes The IFN-gamma therapy improved the clinical severity scores and serum total IgE levels (Fig. 2). The WBC counts were decreased by IFN-gamma therapy, while the blood eosinophil % and
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Fig. 4 (continued)
eosinophil cationic protein levels were not changed by IFN-gamma therapy (Table 1). The specific IgE levels for milk, eggs, soybeans, wheat, Dp and Df were not changed by IFN-gamma therapy.
3.2. Comparison of MSR levels between allergen groups and IFNgamma effects The MSR levels of inhalant allergens were higher than those of foods (Fig. 3). Among inhalant allergens, the MSRs of Dp and Df were the highest, and those of fungi were the lowest (Table 2). The IFN-gamma therapy did not change this pattern of MSR levels among allergen groups.
3.5. IFN-gamma effects on the skin sensitisation index (SSI) The AD patients exhibited a tendency toward an increase in the SSI for allergens, except for foods (Fig. 4c), and IFN-gamma caused the SSI to either decrease or remain unchanged (Table 3c). The SSIs for total allergens increased naturally in the control group and decreased due to IFN-gamma in the treated group. The SSIs for inhalant allergens increased naturally in the control group and decreased due to IFN-gamma therapy in the treated group. The SSIs for food allergens were unchanged in both groups. The SSIs for pollens and danders increased naturally in the control group and decreased due to IFN-gamma therapy in the treated group. The SSIs for fungi and Dp/Df increased naturally in the control group and were unchanged by IFN-gamma therapy in the treated group.
3.3. IFN-gamma effects on the positive item count (PIC) The PICs for total allergens were decreased by the IFN-gamma therapy (Fig. 4a). The PICs for inhalant allergens and food allergens were decreased (Table 3a). Among the inhalant allergens, dander exhibited the most significant PIC decrease due to IFN-gamma therapy. In the case of fungi, the PICs increased in the control group and did not change in the treated group.
3.4. IFN-gamma effects on mean skin reactivity (MSR) MSRs exhibited a tendency to increase in AD patients, and IFNgamma decreased the MSR to total allergens, especially inhalant allergens (Fig. 4b). The MSRs to food allergens were unchanged in both study groups (Table 3b). The MSRs to pollens did not increase in the control group and were decreased by IFN-gamma therapy in the treated group. The MSRs to Dp and Df in the control group increased naturally and did not decrease due to IFN-gamma therapy in the treated group. The MSRs to danders increased naturally in the control group and decreased due to IFN-gamma therapy in the treated group. The MSRs to fungi were unchanged in both groups.
3.6. Correlations between changes in the skin sensitisation profile and serum total IgE levels The changes in the PICs and MSRs were not correlated with changes in serum total IgE levels (Fig. 5). However, the changes in SSIs were significantly correlated with changes in the serum total IgE levels, total allergens, inhalant allergens and food allergens. The changes in the SSIs for inhalant allergens were correlated more significantly with the changes in serum total IgE levels than the changes in the SSIs for foods and total allergens. 4. Discussion IFN-gamma had a polydesensitisation effect in this study (Figs. 4 and 6 and Table 3). In the sensitisation process, the antagonising IgE switching exerted by IFN-gamma through Th2 cytokines, such as IL-4 and IL-5, is well known [11]. Recently, IFN-gamma was demonstrated to exert tolerogenic effects for specific allergens in specific immunotherapy in clinical and experiment reports [5,12]. IFN-gamma has an effect on systemic desensitisation that involves reversal of the skin sensitisation status by reducing the strength of
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Table 3 IFN-gamma effects on skin sensitisation profiles.
⁄
p-value < 0.05.
skin reactivity, as well as the count of sensitised allergens. This role of IFN-gamma in allergen desensitisation is a new concept. Polysensitisation presents a clinical challenge for allergists [13]. The term ‘‘polydesensitisation’’ was first used by Mottard in 1990 [14]. Anti-IgE therapy was utilised for the improvement of polydesensitisation [15]. IFN-gamma was found to exert polydesensitisation effects toward pre-sensitised allergens by non-specific systemic allergen desensitisation. To date, IFN-gamma is the only immunomodulatory drug available for polydesensitisation (PDS) to allergens. In asthma or allergic rhinitis, subcutaneous immunotherapy or sublingual immunotherapy is performed, yielding good results [16,17], while allergen-specific immunotherapy for house dust mites has not been effective in AD [18]. Using IFN-gamma as an adjuvant treatment, desensitisation to house dust mites became
successful in AD patients [4]. Subsequently, by using IFN-gamma, tolerance to IgE-mediated food allergies and non-IgE-mediated food allergies was successfully induced, based on the same theoretical framework [5,6]. The tolerogenic effects of IFN-gamma through regulatory B cells were demonstrated both in vivo and in vitro [12,19]. The specific allergen to be targeted was given alone or with IFN-gamma in allergen-specific immunotherapy. Although the defective IFN-gamma production is allergen-specific in allergic subjects, the immunotherapy effects on IFN-gamma production may be non-specific [20]. The polydesensitisation effect of IFNgamma is non-specific in the absence of specific allergen stimulation, as demonstrated in this study. To induce polydesensitisation, immunotherapy with multiple allergens was attempted [21]. However, it is also an allergen-specific immunotherapy [22]. IFN-gamma is a newly developed drug for systemic polydesensitisation.
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Fig. 5. Correlations between the changes in the skin sensitisation profiles and serum total IgE levels. (a) Correlations between the changes in PCIs for allergen groups and serum total IgE levels, (b) correlations between the changes in MSRs to allergen groups and serum total IgE levels, and (c) correlations between the changes in SSIs for different allergen groups and serum total IgE levels.
Fig. 6. Diagram of the changes in skin sensitisation profiles due to IFN-gamma therapy.
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Allergen-specific immunotherapy induces a Th1 shift in dogs with AD [23]. From our data, it seems that immunotherapy or treatment that increases systemic IFN-gamma production is effective in polydesensitisation and in yielding improvements in allergic diseases. The reduction of serum total IgE levels is an important clinical concern. Long-term treatment with anti-IgE reduced the serum total IgE levels in asthma patients [24]. Furthermore, the serum total IgE levels decreased with IVIG treatment in AD [25,26]. Theoretically, IFN-gamma is expected to reduce the serum total IgE levels because IFN-gamma antagonises IgE switching and immunologically suppresses IgE production. In several reports of clinical trials, IFN-gamma did not reduce the serum total IgE levels, despite improvement in clinical severity [10,27]. Elevated serum total IgE levels were decreased by IFN-gamma therapy (Fig. 2 and Table 1). The difference between the IFN-gamma therapy used in previous reports and the therapy used in this study is that IFN-gamma was used after complete control of food allergies had been obtained in this study. Food allergy control prevents prolonged Th2 activation by food allergy provocation in AD [28]. Under the well-controlled conditions in which prolonged Th2 activation is controlled by complete food allergy control in AD, IFN-gamma reduced serum total IgE levels. Polysensitisation seems to be significantly correlated with serum total IgE levels in this study based on the regression analysis between the changes in the serum total IgE levels and the skin sensitisation index (SSI) (Fig. 5). A strong association between polysensitisation and serum total IgE levels was suggested [29]. With IFN-gamma therapy, serum total IgE levels were decreased with polydesensitisation. The progression of polysensitisation seems to be one of the causes of the elevated serum total IgE levels. There has been a debate regarding the IFN-gamma effects in AD [1,10,27]. The degree of sensitisation to aeroallergens was associated with the severity of AD [30]. IFN-gamma improves skin sensitisation status, as well as clinical severity (Figs. 2 and 4 and Tables 1 and 2). The clinical severity improvement due to IFN-gamma seems to be related to polydesensitisation and the consequent reduction of serum total IgE levels. Until now, it was not possible to improve clinical severity by reducing the total serum IgE levels. IFN-gamma is indicated in AD patients whose food allergies are well controlled and who are polysensitised to multiple allergens, as evidenced by a high serum total IgE level. The skin is more sensitised to inhalant allergens than to food allergens (Fig. 3 and Table 2). Different patterns of sensitisation to foods and inhalant allergens with regard to the number of sensitisations were also reported [29]. The degree of sensitisation was different between foods and inhalant allergens in this study. Among inhalant allergens, house dust mites seem to exert the greatest degree of sensitivity, and fungi seem to exert the least degree of sensitivity. IFN-gamma did not change the characteristic patterns of the degree of sensitisation of various allergen groups. The effects of IFN-gamma on polydesensitisation patterns differed according to the allergen group. This difference seems to be due to the degree of skin reactivity to allergens, as well as to their own allergenic characteristics [29]. IFN-gamma effects appeared to decrease skin sensitisation or prevent skin sensitisation differently according to the allergen group (Figs. 3 and 6 and Table 2). IFNgamma prevented further sensitisation to house dust mites and fungi, while IFN-gamma improved skin sensitisation to pollens. In the case of danders, IFN-gamma both prevented and improved skin sensitisation. IFN-gamma was reported to prevent allergic polysensitisation in children [31]. IFN-gamma seems to be effective for the prevention, as well as improvement, of skin sensitisation to inhalant allergens. The use of certain indices, such as the atopy profile or allergic index, was suggested to evaluate polysensitisation [32,33]. Polysensitisation was evaluated according to the number of positive
allergens [29]. For foods, the change in sensitisation status was not detected exclusively by PIC or MSR, but it was detected by the SSI, a newly developed sensitisation index (Figs. 3 and 6). The polysensitisation status seems to be precisely identified using these three skin sensitisation profiles. The status of polysensitisation and polydesensitisation due to IFN-gamma was well described using the skin sensitisation profiles in this study (Figs. 3 and 6). The significant level of variation in blood tests and sensitised allergen parameters represents a limitation of this preliminary study. Future studies should be extended to include more homogenous subjects to address this issue. Conclusively, IFN-gamma resulted in systemic polydesensitisation and reducing elevated serum total IgE levels. Polydesensitisation is the only method for reducing serum total IgE levels. IFN-gamma prevented further sensitisation to multiple allergens. IFN-gamma is indicated in AD patients whose food allergies are well controlled and who are polysensitised to multiple allergens, as evidenced by high serum total IgE levels, as well as in AD for the prevention of allergic polysensitisation. For the proper evaluation of polysensitisation status, skin sensitisation profiles are necessary, and the skin sensitisation index is especially appropriate for this purpose. Acknowledgements This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (20120008388). Especially, I would like to express special thanks to Yea Hee Yoo (C), my wife, for her help in completing this study. I also wish to acknowledge my lovely son, Chan-Yong (brilliant dragon) Noh, who was born during the preparation of this manuscript. References [1] Lee J, Noh G, Lee S, Youn Y, Rhim J. Atopic dermatitis and cytokines: recent patents in immunoregulatory and therapeutic implications of cytokines in atopic dermatitis – Part I: Cytokines in atopic dermatitis. Recent Pat Inflamm Allergy Drug Discov 2012;6:222–47. [2] Verstege A, Mehl A, Rolinck-Werninghaus C, et al. The predictive value of the SPT wheal size for the outcome of oral food challenge. Clin Exp Allergy 2005;35:1220–6. [3] Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891–6. [4] Noh G, Lee KY. Pilot study of IFN-gamma-induced specific hyposensitisation for house dust mites in atopic dermatitis: IFN-gamma-induced immune deviation as a new therapeutic concept for atopic dermatitis. Cytokine 2000;12:472–6. [5] Noh G, Lee SS. A pilot study of interferon-gamma-induced specific oral tolerance induction (ISOTI) for immunoglobulin E-mediated anaphylactic food allergy. J Interferon Cytokine Res 2009;29:667–75. [6] Lee JH, Noh G, Noh J, Lee SJ, Choi WS, Kim HS, et al. Clinical characteristics of oral tolerance induction of IgE-mediated and non-IgE-mediated food allergy using interferon gamma. Allergy Asthma Proc 2010;31:e39–47. [7] Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980;92:44–7. [8] Carlsen BC, Andersen KE, Menné T, Johansen JD. Characterization of the polysensitized patient: a matched case-control study. Contact Dermatitis 2009;61:22–30. [9] Sprikkelman AB, Tupker RA, Burgerhof H, et al. Severity scoring of atopic dermatitis: a comparison of three scoring systems. Allergy 1997;52:944–9. [10] Noh GW, Lee KY. Blood eosinophils and serum IgE as predictors for prognosis of interferon-gamma therapy in atopic dermatitis. Allergy 1998;53:1202–7. [11] Maggi E, Del Prete GF, Tiri A, Macchia D, Parronchi P, Ricci M, et al. Role of interleukin-4 in the induction of human IgE synthesis and its suppression by interferon-gamma. Ric Clin Lab 1987;17:363–7. [12] Noh J, Noh G, Lee SJ, Lee JH, Kim A, Choi KimHS, et al. Tolerogenic effects of interferon-gamma with induction of allergen-specific interleukin-10producing regulatory B cell (Br1) changes in non-IgE-mediated food allergy. Cell Immunol 2012;273:140–9. [13] Ciprandi G, Incorvaia C, Puccinelli P, Soffia S, Scurati S, Frati F. Polysensitisation as a challenge for the allergist: the suggestions provided by the polysensitisation Impact on Allergen Immunotherapy studies. Expert Opin Biol Ther 2011;11:715–22.
J.H. Lee, G. Noh / Cytokine 64 (2013) 395–403 [14] Mottard L. A special immunotherapeutic practice: polydesensitisation or simultaneous multiple desensitisations. A 30-year experience. Rev Med Liege 1990;45:638–48. [15] Pichler WJ. Specific and nonspecific (anti-IgE) immunotherapy of allergic diseases. Ther Umsch 2001;58:329–36. [16] Klimek L, Schendzielorz P, Pinol R, Pfaar O. Specific subcutaneous immunotherapy with recombinant grass pollen allergens: first randomized dose-ranging safety study. Clin Exp Allergy 2012;42:936–45. [17] Di Bona D, Plaia A, Leto-Barone MS, La Piana S, Di Lorenzo G. Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A meta-analysis-based comparison. J Allergy Clin Immunol 2012;5:1097–107. [18] Glover MT, Atherton DJ. A double-blind controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with atopic eczema. Clin Exp Allergy 1992;22:440–4. [19] Lee SJ, Noh G, Lee JH. In vitro induction of allergen-specific interleukin-10producing regulatory B cell responses by interferon-c in non-immunoglobulin E-mediated milk allergy. Allergy Asthma Immunol Res 2012;4:e133. [20] Ciprandi G, Sormani MP, Filaci G, Fenoglio D. Carry-over effect on IFN-gamma production induced by allergen-specific immunotherapy. Int Immunopharmacol 2008;8:1622–5. [21] Nelson HS. Multiallergen immunotherapy for allergic rhinitis and asthma. J Allergy Clin Immunol 2009;123:763–9. [22] Calderón MA, Cox L, Casale TB, Moingeon P, Demoly P. Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: looking at the published evidence. J Allergy Clin Immunol 2012;129:929–34. [23] Shida M, Kadoya M, Park SJ, Nishifuji K, Momoi Y, Iwasaki T. Allergen-specific immunotherapy induces Th2 shift in dogs with atopic dermatitis. Vet Immunol Immunopathol 2004;102:19–31.
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Contents lists available at SciVerse ScienceDirect
Cytokine journal homepage: www.journals.elsevier.com/cytokine
Polydesensitisation with reducing elevated serum total IgE by IFN-gamma therapy in atopic dermatitis: IFN-gamma and polydesensitisation (PDS) Jae Ho Lee a, Geunwoong Noh b,c,⇑ a b c
Department of Paediatrics, Chungnam National University, Dajeon, Republic of Korea Department of Paediatrics & International Allergy Centre, Pyeongtaek International Hospital, Pyeongtaek, Republic of Korea Seoul Allergy Clinic, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 27 November 2012 Received in revised form 21 March 2013 Accepted 17 May 2013 Available online 17 June 2013 Keywords: IFN-gamma Polydesensitisation Serum total IgE Atopic dermatitis
a b s t r a c t Background: AD patients exhibit sensitisation to multiple allergens due to a Th1/Th2 imbalance. Until now, it was impossible to improve the polysensitised status and elevated serum total IgE levels. In this study, the effects of IFN-gamma on systemic polysensitisation to multiple allergens and on serum total IgE levels are investigated. Methods: A total of 44 AD patients whose food allergies were completely controlled and who were polysensitised to multiple allergens according to the SPT were selected. Twenty-two of these patients received IFN-gamma therapy twice a week for 2 months, and 22 patients did not receive this therapy. The blood eosinophil % and serum total IgE levels were assessed, and a skin prick test for 51 allergens was performed before and after the IFN-gamma therapy. Results: With IFN-gamma therapy, the polysensitisation status was improved, as demonstrated by a decrease in the positive allergen count and skin reactivity (systemic polydesensitisation). The improvement in the polysensitised status was accompanied by a decrease in serum total IgE levels. The change in serum total IgE levels was significantly correlated with the change in polysensitisation status. Conclusions: IFN-gamma therapy resulted in systemic polydesensitisation with reduced levels of serum total IgE. IFN-gamma is indicated in AD patients with high serum total IgE levels whose food allergies are well controlled and who are polysensitised to multiple allergens. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Atopic dermatitis is a chronic relapsing allergic skin disease that is characterised by advanced eczematous skin lesions. The basic immunopathogenesis associated with the development of atopic dermatitis is a Th1/Th2 imbalance with consequent allergy sensitisation and the acquisition of an allergy to a specific allergen, including a food allergen and/or aeroallergen [1]. As a result of an allergenic sensitisation, the skin prick test and allergen-specific IgE levels become positive [2,3]. IFN-gamma is a Th1 cytokine and is known to have anti-allergic properties [1]. During the process of antigen sensitisation, IFNAbbreviations: PDS, polydesensitisation; IFN-c, interferon-gamma; SPT, skin prick test; AD, atopic dermatitis; Dp, dermatophagoides pteronyssinus; Df, dermatophagoides farinae. ⇑ Corresponding author. Address: Department of Paediatrics and International Allergy Centre, Pyeongtaek International Hospital, 109 Bangchuk-gil, Godeokmyeon, Pyeongtaek, Gyeonggi Province 451-841, Republic of Korea. Tel.: +82 2 540 4923; fax: +82 2 511 2667. E-mail address: [email protected] (G. Noh). 1043-4666/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2013.05.011
gamma leads to Th1 immune responses, and Th2 cytokines, including IL-4 and IL-5, lead to Th2 immune responses. Allergen-specific immunotherapy with IFN-gamma has been shown to have tolerogenic effects for certain allergens, including house dust mites and food allergens [4–6]. In this study, we investigated the effects of systemic administration of IFN-gamma on the desensitisation of multiple allergens without the introduction of specific allergens. A new concept of polydesensitisation (PDS) is suggested. 2. Patients and methods 2.1. Subjects and study design The study subjects consisted of 44 patients who visited the Department of Allergy and Clinical Immunology at the Seoul Allergy Clinic (Seoul, Korea) and met the Hanifin and Rajka criteria [7]. The mean patient age was 19.6 ± 12.7 years (M:F = 23:21) (Fig. 1). The patients’ food allergies had been controlled for at least 6 months, as described in the previous report [6], and they were polysensitised to multiple allergens, as demonstrated by the SPT.
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Fig. 1. Study design. Patients whose food allergies were completely controlled and who were polysensitised to multiple allergens, as evidenced by high serum total IgE levels, were selected. Laboratory tests used to determine clinical severity scores were performed before and after IFN-gamma therapy.
Polysensitisation was defined in the previous report as sensitivity to three or more allergens [8]. Among the 44 subjects, 22 patients (mean age = 18.2 ± 9.4 years, M:F = 11:11) received IFN-gamma therapy as scheduled, and the 22 patients (mean age = 20.8 ± 14.3 years, M:F = 12:10) in the control group were untreated. All subjects received a blood test and skin prick test (SPT) before and after the IFN-gamma therapy. The tests included complete blood counts and an assessment of differential serum total IgE, serum eosinophil cationic protein (ECP) and IgE levels for specific allergens. A SPT was performed for 50 allergens, including pollens, fungi, danders, Dp/Df and food allergens. The clinical severity was evaluated before and after the intervention using the SCORing Atopic Dermatitis (SCORAD) index, which is used worldwide to assess the severity of atopic eczema [9]. The subjects or their parents signed consent forms that included information concerning this study, especially information regarding the possibility of an emergency situation due to acute anaphylactic reactions to the oral challenge tests. The study was approved by the Ethics Committee of Chungnam National University Hospital, Daejeon, Korea. 2.2. Blood tests and SPT Blood testing on each patient included a CBC with differential counts for the eosinophil fraction, serum total IgE levels, and spe-
cific IgE for milk, eggs, soybeans, wheat, Dp and Df. These tests were conducted before and after the tolerance induction. Foodspecific IgE levels were measured using the UniCapÒ (Pharmacia & Upjohn Diagnostics AB, Uppsala, Sweden) method. The SPTs were conducted on the patients’ left forearms using commercial allergen extracts (Bencard, Brentford, England). Histamine hydrochloride (1 mg/ml) (Bencard) was used as a positive control. Physiologic saline, distilled water, and glycerol were used as negative controls. A minimum wheal size of 3 mm was used to indicate a positive reaction to histamine, and the ratios of the wheal sizes resulting from the allergens to the wheal size resulting from histamine were calculated.
2.3. IFN-gamma therapy Patients received an IFN-c injection three times a week for 8 weeks. Recombinant IFN-c (Intermax gamma, LGCI, Seoul, Korea), with a specific activity of 2 106 IU (50 mg), was administered by subcutaneous injection at a dose of 3 106 IU/m2 according to the body surface area, as previously reported [10]. Although the patients were instructed to take oral acetaminophen (10 mg/kg, up to a maximum dose of 600 mg) twice, at 1 h and 4 h after the injection, to reduce the possibility of side effects (e.g., myalgia, fever, or flu-like symptoms), none of the subjects exhibited symptoms or took oral acetaminophen.
2.4. Skin sensitisation profiles Three skin sensitisation profiles were used for the evaluation of the polysensitisation status and polydesensitisation effects of IFNgamma. A positive item count refers to the number of items that yield positive SPT results. The mean skin reactivity is the average of the grade of the skin prick test for all positive allergens. The grade of the skin prick test was calculated by the ratio of the wheal size for allergens to the wheal size for histamine. The skin sensitisation index is the sum of the score of the skin prick test for all positive allergens.
Fig. 2. Clinical and laboratory changes induced by IFN-gamma therapy. (a) Clinical severity scores, (b) WBC counts, (c) blood eosinophil percentages, and (d) serum total IgE levels.
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Table 1 Clinical and laboratory changes induced by IFN-gamma.
⁄
p-value < 0.05.
Fig. 3. Levels of MSR to various allergens and IFN-gamma effects. MSR levels in: (a) total patients before the intervention, (b) total patients after the intervention, (c) treated patients after the intervention, and (d) control patients after the intervention.
Table 2 Characteristics of MSR to various allergens before and after IFN-gamma therapy.
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Fig. 4. IFN-gamma effects on skin sensitisation profiles. (a) Positive item counts (PICs) for allergen groups, (b) mean skin reactivity (MSR) to allergen groups, and (c) skin sensitisation index (SSI) for allergen groups.
2.5. Statistical analysis The mean and standard deviations were calculated for comparison of the results before and after the intervention using the Wilcoxon signed-rank test and paired t-test to evaluate the effects of the IFN-gamma therapy. The Kruskal–Wallis one-way analysis of variance on ranks was performed to compare the difference of the means of MSR between the allergen groups. A linear regression was performed to analyse the relationship between changes in the skin sensitisation profiles and serum total IgE levels. P-values < 0.05 were considered significant. The statistical analysis
was performed using SigmaPlot software (Systat Software Inc., San Jose, CA, USA).
3. Results 3.1. IFN-gamma effects on clinical severity and laboratory changes The IFN-gamma therapy improved the clinical severity scores and serum total IgE levels (Fig. 2). The WBC counts were decreased by IFN-gamma therapy, while the blood eosinophil % and
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Fig. 4 (continued)
eosinophil cationic protein levels were not changed by IFN-gamma therapy (Table 1). The specific IgE levels for milk, eggs, soybeans, wheat, Dp and Df were not changed by IFN-gamma therapy.
3.2. Comparison of MSR levels between allergen groups and IFNgamma effects The MSR levels of inhalant allergens were higher than those of foods (Fig. 3). Among inhalant allergens, the MSRs of Dp and Df were the highest, and those of fungi were the lowest (Table 2). The IFN-gamma therapy did not change this pattern of MSR levels among allergen groups.
3.5. IFN-gamma effects on the skin sensitisation index (SSI) The AD patients exhibited a tendency toward an increase in the SSI for allergens, except for foods (Fig. 4c), and IFN-gamma caused the SSI to either decrease or remain unchanged (Table 3c). The SSIs for total allergens increased naturally in the control group and decreased due to IFN-gamma in the treated group. The SSIs for inhalant allergens increased naturally in the control group and decreased due to IFN-gamma therapy in the treated group. The SSIs for food allergens were unchanged in both groups. The SSIs for pollens and danders increased naturally in the control group and decreased due to IFN-gamma therapy in the treated group. The SSIs for fungi and Dp/Df increased naturally in the control group and were unchanged by IFN-gamma therapy in the treated group.
3.3. IFN-gamma effects on the positive item count (PIC) The PICs for total allergens were decreased by the IFN-gamma therapy (Fig. 4a). The PICs for inhalant allergens and food allergens were decreased (Table 3a). Among the inhalant allergens, dander exhibited the most significant PIC decrease due to IFN-gamma therapy. In the case of fungi, the PICs increased in the control group and did not change in the treated group.
3.4. IFN-gamma effects on mean skin reactivity (MSR) MSRs exhibited a tendency to increase in AD patients, and IFNgamma decreased the MSR to total allergens, especially inhalant allergens (Fig. 4b). The MSRs to food allergens were unchanged in both study groups (Table 3b). The MSRs to pollens did not increase in the control group and were decreased by IFN-gamma therapy in the treated group. The MSRs to Dp and Df in the control group increased naturally and did not decrease due to IFN-gamma therapy in the treated group. The MSRs to danders increased naturally in the control group and decreased due to IFN-gamma therapy in the treated group. The MSRs to fungi were unchanged in both groups.
3.6. Correlations between changes in the skin sensitisation profile and serum total IgE levels The changes in the PICs and MSRs were not correlated with changes in serum total IgE levels (Fig. 5). However, the changes in SSIs were significantly correlated with changes in the serum total IgE levels, total allergens, inhalant allergens and food allergens. The changes in the SSIs for inhalant allergens were correlated more significantly with the changes in serum total IgE levels than the changes in the SSIs for foods and total allergens. 4. Discussion IFN-gamma had a polydesensitisation effect in this study (Figs. 4 and 6 and Table 3). In the sensitisation process, the antagonising IgE switching exerted by IFN-gamma through Th2 cytokines, such as IL-4 and IL-5, is well known [11]. Recently, IFN-gamma was demonstrated to exert tolerogenic effects for specific allergens in specific immunotherapy in clinical and experiment reports [5,12]. IFN-gamma has an effect on systemic desensitisation that involves reversal of the skin sensitisation status by reducing the strength of
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Table 3 IFN-gamma effects on skin sensitisation profiles.
⁄
p-value < 0.05.
skin reactivity, as well as the count of sensitised allergens. This role of IFN-gamma in allergen desensitisation is a new concept. Polysensitisation presents a clinical challenge for allergists [13]. The term ‘‘polydesensitisation’’ was first used by Mottard in 1990 [14]. Anti-IgE therapy was utilised for the improvement of polydesensitisation [15]. IFN-gamma was found to exert polydesensitisation effects toward pre-sensitised allergens by non-specific systemic allergen desensitisation. To date, IFN-gamma is the only immunomodulatory drug available for polydesensitisation (PDS) to allergens. In asthma or allergic rhinitis, subcutaneous immunotherapy or sublingual immunotherapy is performed, yielding good results [16,17], while allergen-specific immunotherapy for house dust mites has not been effective in AD [18]. Using IFN-gamma as an adjuvant treatment, desensitisation to house dust mites became
successful in AD patients [4]. Subsequently, by using IFN-gamma, tolerance to IgE-mediated food allergies and non-IgE-mediated food allergies was successfully induced, based on the same theoretical framework [5,6]. The tolerogenic effects of IFN-gamma through regulatory B cells were demonstrated both in vivo and in vitro [12,19]. The specific allergen to be targeted was given alone or with IFN-gamma in allergen-specific immunotherapy. Although the defective IFN-gamma production is allergen-specific in allergic subjects, the immunotherapy effects on IFN-gamma production may be non-specific [20]. The polydesensitisation effect of IFNgamma is non-specific in the absence of specific allergen stimulation, as demonstrated in this study. To induce polydesensitisation, immunotherapy with multiple allergens was attempted [21]. However, it is also an allergen-specific immunotherapy [22]. IFN-gamma is a newly developed drug for systemic polydesensitisation.
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Fig. 5. Correlations between the changes in the skin sensitisation profiles and serum total IgE levels. (a) Correlations between the changes in PCIs for allergen groups and serum total IgE levels, (b) correlations between the changes in MSRs to allergen groups and serum total IgE levels, and (c) correlations between the changes in SSIs for different allergen groups and serum total IgE levels.
Fig. 6. Diagram of the changes in skin sensitisation profiles due to IFN-gamma therapy.
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Allergen-specific immunotherapy induces a Th1 shift in dogs with AD [23]. From our data, it seems that immunotherapy or treatment that increases systemic IFN-gamma production is effective in polydesensitisation and in yielding improvements in allergic diseases. The reduction of serum total IgE levels is an important clinical concern. Long-term treatment with anti-IgE reduced the serum total IgE levels in asthma patients [24]. Furthermore, the serum total IgE levels decreased with IVIG treatment in AD [25,26]. Theoretically, IFN-gamma is expected to reduce the serum total IgE levels because IFN-gamma antagonises IgE switching and immunologically suppresses IgE production. In several reports of clinical trials, IFN-gamma did not reduce the serum total IgE levels, despite improvement in clinical severity [10,27]. Elevated serum total IgE levels were decreased by IFN-gamma therapy (Fig. 2 and Table 1). The difference between the IFN-gamma therapy used in previous reports and the therapy used in this study is that IFN-gamma was used after complete control of food allergies had been obtained in this study. Food allergy control prevents prolonged Th2 activation by food allergy provocation in AD [28]. Under the well-controlled conditions in which prolonged Th2 activation is controlled by complete food allergy control in AD, IFN-gamma reduced serum total IgE levels. Polysensitisation seems to be significantly correlated with serum total IgE levels in this study based on the regression analysis between the changes in the serum total IgE levels and the skin sensitisation index (SSI) (Fig. 5). A strong association between polysensitisation and serum total IgE levels was suggested [29]. With IFN-gamma therapy, serum total IgE levels were decreased with polydesensitisation. The progression of polysensitisation seems to be one of the causes of the elevated serum total IgE levels. There has been a debate regarding the IFN-gamma effects in AD [1,10,27]. The degree of sensitisation to aeroallergens was associated with the severity of AD [30]. IFN-gamma improves skin sensitisation status, as well as clinical severity (Figs. 2 and 4 and Tables 1 and 2). The clinical severity improvement due to IFN-gamma seems to be related to polydesensitisation and the consequent reduction of serum total IgE levels. Until now, it was not possible to improve clinical severity by reducing the total serum IgE levels. IFN-gamma is indicated in AD patients whose food allergies are well controlled and who are polysensitised to multiple allergens, as evidenced by a high serum total IgE level. The skin is more sensitised to inhalant allergens than to food allergens (Fig. 3 and Table 2). Different patterns of sensitisation to foods and inhalant allergens with regard to the number of sensitisations were also reported [29]. The degree of sensitisation was different between foods and inhalant allergens in this study. Among inhalant allergens, house dust mites seem to exert the greatest degree of sensitivity, and fungi seem to exert the least degree of sensitivity. IFN-gamma did not change the characteristic patterns of the degree of sensitisation of various allergen groups. The effects of IFN-gamma on polydesensitisation patterns differed according to the allergen group. This difference seems to be due to the degree of skin reactivity to allergens, as well as to their own allergenic characteristics [29]. IFN-gamma effects appeared to decrease skin sensitisation or prevent skin sensitisation differently according to the allergen group (Figs. 3 and 6 and Table 2). IFNgamma prevented further sensitisation to house dust mites and fungi, while IFN-gamma improved skin sensitisation to pollens. In the case of danders, IFN-gamma both prevented and improved skin sensitisation. IFN-gamma was reported to prevent allergic polysensitisation in children [31]. IFN-gamma seems to be effective for the prevention, as well as improvement, of skin sensitisation to inhalant allergens. The use of certain indices, such as the atopy profile or allergic index, was suggested to evaluate polysensitisation [32,33]. Polysensitisation was evaluated according to the number of positive
allergens [29]. For foods, the change in sensitisation status was not detected exclusively by PIC or MSR, but it was detected by the SSI, a newly developed sensitisation index (Figs. 3 and 6). The polysensitisation status seems to be precisely identified using these three skin sensitisation profiles. The status of polysensitisation and polydesensitisation due to IFN-gamma was well described using the skin sensitisation profiles in this study (Figs. 3 and 6). The significant level of variation in blood tests and sensitised allergen parameters represents a limitation of this preliminary study. Future studies should be extended to include more homogenous subjects to address this issue. Conclusively, IFN-gamma resulted in systemic polydesensitisation and reducing elevated serum total IgE levels. Polydesensitisation is the only method for reducing serum total IgE levels. IFN-gamma prevented further sensitisation to multiple allergens. IFN-gamma is indicated in AD patients whose food allergies are well controlled and who are polysensitised to multiple allergens, as evidenced by high serum total IgE levels, as well as in AD for the prevention of allergic polysensitisation. For the proper evaluation of polysensitisation status, skin sensitisation profiles are necessary, and the skin sensitisation index is especially appropriate for this purpose. Acknowledgements This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (20120008388). Especially, I would like to express special thanks to Yea Hee Yoo (C), my wife, for her help in completing this study. I also wish to acknowledge my lovely son, Chan-Yong (brilliant dragon) Noh, who was born during the preparation of this manuscript. References [1] Lee J, Noh G, Lee S, Youn Y, Rhim J. Atopic dermatitis and cytokines: recent patents in immunoregulatory and therapeutic implications of cytokines in atopic dermatitis – Part I: Cytokines in atopic dermatitis. Recent Pat Inflamm Allergy Drug Discov 2012;6:222–47. [2] Verstege A, Mehl A, Rolinck-Werninghaus C, et al. The predictive value of the SPT wheal size for the outcome of oral food challenge. Clin Exp Allergy 2005;35:1220–6. [3] Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891–6. [4] Noh G, Lee KY. Pilot study of IFN-gamma-induced specific hyposensitisation for house dust mites in atopic dermatitis: IFN-gamma-induced immune deviation as a new therapeutic concept for atopic dermatitis. Cytokine 2000;12:472–6. [5] Noh G, Lee SS. A pilot study of interferon-gamma-induced specific oral tolerance induction (ISOTI) for immunoglobulin E-mediated anaphylactic food allergy. J Interferon Cytokine Res 2009;29:667–75. [6] Lee JH, Noh G, Noh J, Lee SJ, Choi WS, Kim HS, et al. Clinical characteristics of oral tolerance induction of IgE-mediated and non-IgE-mediated food allergy using interferon gamma. Allergy Asthma Proc 2010;31:e39–47. [7] Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980;92:44–7. [8] Carlsen BC, Andersen KE, Menné T, Johansen JD. Characterization of the polysensitized patient: a matched case-control study. Contact Dermatitis 2009;61:22–30. [9] Sprikkelman AB, Tupker RA, Burgerhof H, et al. Severity scoring of atopic dermatitis: a comparison of three scoring systems. Allergy 1997;52:944–9. [10] Noh GW, Lee KY. Blood eosinophils and serum IgE as predictors for prognosis of interferon-gamma therapy in atopic dermatitis. Allergy 1998;53:1202–7. [11] Maggi E, Del Prete GF, Tiri A, Macchia D, Parronchi P, Ricci M, et al. Role of interleukin-4 in the induction of human IgE synthesis and its suppression by interferon-gamma. Ric Clin Lab 1987;17:363–7. [12] Noh J, Noh G, Lee SJ, Lee JH, Kim A, Choi KimHS, et al. Tolerogenic effects of interferon-gamma with induction of allergen-specific interleukin-10producing regulatory B cell (Br1) changes in non-IgE-mediated food allergy. Cell Immunol 2012;273:140–9. [13] Ciprandi G, Incorvaia C, Puccinelli P, Soffia S, Scurati S, Frati F. Polysensitisation as a challenge for the allergist: the suggestions provided by the polysensitisation Impact on Allergen Immunotherapy studies. Expert Opin Biol Ther 2011;11:715–22.
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