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1 Od redakcji Ten specjalny numer Alergologii Współczesnej jest wydany z okazji konferencji, poświęconej problemom immunoterapii swoistej, która odbędzie się w Krakowie w dniach października 2005 roku. Proponujemy, by zapoznali się Państwo z obszernymi streszczeniami wystąpień wybitnych wykładowców z kraju i zagranicy. Materiał ten obejmuje wiele zagadnień wspólczesnej alergologii i immunoterapii swoistej. Spis treści Contents prof. dr hab. med. K. Jahnz Różyk Od redakcji; Editorial str. 1 Detailed contents; Szczegółowy spis treści.... str. 2 English articles; artykuły w języku angielskim str. 3 Polish articles; artykuły w języku polskim str. 28 Prof. Karina Jahnz-Różyk Redaktor Naczelna Editorial This special edition of Allergologia Współczesna has been issued particularly for the science conference focused on problems with specific immunotherapy (Kraków, October 2005). The aim of this publication is to let You read up all the comprehensive summaries of lectures which will be given by the most prominent scientists from many countries, also from Poland. The material includes many issues of modern allergology and specific immunotherapy. Prof. Karina Jahnz-Różyk Editor in Chief Wydawca: NEXTER Sp. z o. o. ul Jordana 7b Katowice tel. (0-32) fax (0-32) http//www.nexter.pl NEXTER Sp. z o. o. jest autoryzowanym dystrybutorem firmy Allergopharma Skład, redakcja techniczna, korekta: ARTIS, tel onet. pl Druk: Drukarnia TriadaPress K-ce, ul. Wandy 14 tel. (032) ISSN

2 Strona 2 Alergologia Współczesna nr 2 (16) Detailed contents Szczegółowy spis treści English articles artykuły w języku angielskim Safety of immunotherapy- Prof. dr. G. Schultze-Werninghaus Long-term efficacy in specific immunotherapy- PD dr. P.A. Eng Efficacy and safety of pre-seasonal specific immunotherapy with an aluminium-adsorbed 6-grass pollen allergoid Dr. C.J. Corrigan Clinical efficacy of mite allergoid preparation Prof. dr. A.J. Frew How efficacious is sublingual therapy?- PD dr. J. Kleine-Tebbe The immunopathogenesis of Atopic Dermatitis Mrs. Dr. dr. M. Akdis Specific immunotherapy in atopic dermatitis general consideration- PD dr. U. Darsow, Prof. dr. J. Ring Specific immunotherapy in atopic dermatitis : DBPC study Prof. dr. W. Silny, MD Ph.D. M. Czarnecka-Operacz Major allergens are best representative allergens? Dr. A. Mari Potential benefits of recombinant allergens Dr. O. Cromwell Specific immunotherapy with recombinant grass pollen allergen cocktail- Prof. dr. M. Jutel Production and standardisation of mould extracts Dr. F.M. Kniest SIT in mould allergies Prof. dr. P. Kuna Nasal provocation test in upper airway disease position statement of German Society of Allergy and Clinical Immunology Comparison of conjunctival and nasal provocation test in allergic rhinitis to house dust mites Prof. dr. H. Riechelmann Comparison of specific IgE measurements (Allergen Dipstick Allergodip Mites and More) with skin-prick-test and nasal provocation in house dust mite and storage mite allergic patients Dr. A. Stanek Insect Venom Immunotherapy Prof. dr. B. Przybilla Pharmacoeconomic evaluations of specific immunotherapy (SIT)- Dr. P.K. Schädlich Polish articles artykuły w języku polskim Bezpieczeństwo immunoterapii Prof. dr G. Schultze-Werninghaus Długotrwała skuteczność immunoterapii swoistej PD dr P.A. Eng Skuteczność i bezpieczeństwo przedsezonowej immunoterapii swoistej alergoidem pyłku 6 traw adsorbowanym na wodorotlenku glinu Dr C. J. Corrigan Skuteczność kliniczna alergoidów roztoczowych Prof. dr A. J. Frew Jak skuteczna jest terapia podjęzykowa? PD dr J. Kleine-Tebbe Immunopatogeneza atopowego zapalenia skóry Dr dr M. Akdis Immunoterapia swoista atopowym zapaleniu skóry uwagi ogólne PD dr U. Darsow, Prof. dr J. Ring Immunoterapia swoista w leczeniu atopowego zapalenia skóry : wyniki badania przeprowadzonego w warunkach próby podwójnie ślepej kontrolowanej placebo Prof. dr hab. W. Silny, Dr hab. M. Czarnecka-Operacz Alergeny główne czy najbardziej reprezentatywne? Dr A. Mari Potencjalne korzyści alergenów rekombinowanych Dr O. Cromwell Immunoterapia swoista z użyciem mieszanki rekombinowanych alergenów traw Prof. dr hab. M. Jutel Produkcja i standaryzacja wyciągów grzybów Dr F. M. Kniest SIT w alergiach na grzyby pleśniowe Prof. dr hab. P. Kuna Donosowe próby prowokacyjne w diagnostyce chorób górnych dróg oddechowych - stanowisko Niemieckiego Towarzystwa Alergologii i Immunologii Klinicznej Porównanie testów prowokacyjnych dospojówkowych i donosowych w alergicznym nieżycie nosa u chorych uczulonych na roztocza kurzu domowego Prof. dr H. Riechelmann Porównanie pomiarów swoistych IgE (alergenowym testem paskowym Allergodip Mites and More) z punktowymi testami skórnymi i prowokacją donosową u pacjentów uczulonych na roztocza kurzu domowego i spiżarniane Dr A.Stanek Immunoterapia jadami owadów błonkoskrzydłych Prof. dr B. Przybilla Ocena farmakoekonomiczna immunoterapii swoistej (SIT) Dr P. K. Schädlich Nagroda Allergopharmy przyznana po raz piąty! Streszczenia prac nad nowymi preparatami terapeutycznymi firmy Allergopharma zaprezentowane podczas Kongresu EAACI/WAO w dn r. w Monachium Immunoterapia swoista alergoidami trwały efekt, skuteczność i bezpieczeństwo Dr S. Thum-Oltmer, Dr J. Nizio-Mąsior

3 Safety of Specific Immunotherapy Gerhard Schultze-Werninghaus University Hospital Bergmannsheil, Ruhr-University Bochum Dept. of Internal Medicine III Pneumology, Allergology, and Sleep Medicine Bürkle-de-la-Camp-Platz 1 D Bochum Subcutaneous allergen immunotherapy (SIT) has been used for more than 90 years for the management of allergic rhinitis, allergic asthma and hymenoptera sensitivity. Substantial progress has been made in the quality of allergen extracts. However, there is still one major concern, regarding SIT: namely the safety of allergen injections. Lüderitz-Püchel et al. published in 2001 adverse drug reactions (ADR) to diagnostic and therapeutic allergen extracts that had been reported between 1991 and 2000 to the Paul-Ehrlich-Institute, Langen, Germany. Only ADR that were categorized as serious according to international definitions and which had at least a possible causal relationship with the usage of diagnostic and therapeutic allergen extracts, were included in the analysis. 555 life-threatening reactions after subcutaneous injection had been reported. Three incidences with fatal outcome were registered. Serious ADR after SIT were analysed separately for two time-periods, 1991 to 1995 and 1996 to 2000, respectively. The comparison of the two time periods showed a reduction of approximately 25 % of registered serious ADRs. 88 % of the ADRs occurred within 30 minutes, 12% after 30 minutes to up to 24 hrs. 230 ADRs were seen after injection of conventional allergen extracts, 225 after modified preparations (allergoids). 75 % of delayed ADRs were caused by no modified extracts, 25 % by allergoids. There was no relation to the specific allergen used for SIT. 24% of ADRs occurred during maintenance therapy ( ). Approximately 37% of the 555 serious adverse drug reactions were considered avoidable. Asthma was reported in 79/238 ADRs between 1996 and The authors concluded that special care (drug treatment, lung function controls, FEV 1 > 70%) is necessary when SIT is given to asthmatic subjects. The three fatal cases were all more than 40 years old, and had had anaphylaxis, shock and severe asthma with temporal relation to allergen injection. The description of these cases is not detailed enough to allow firm conclusions about the causes of death. The authors calculated the incidence of ADRs with relation to the estimated numbers of SIT packages used between 1991 and They calculated 0.02 to % of non-fatal serious ADRs per unmodified semidepot preparation sold, and to [mean: ] per injection. For allergoids they calculated [corrected data] to 0.01 % per injection [mean: ]. This would mean that a serious ADR has an incidence of one in injections. The incidence of anaphylactic shock was estimated to be 1 in to injections, ie one shock in % of all injections. SIT in hymenoptera sensitivity is also relatively safe. Mosebach und Muller reported in 2000 data from a prospective study in 19 European centers, with 840 patients and a total of injections. Twenty percent of patients had systemic effects corresponding to 1.9% of injections during dose increase and 0.5% during the maintenance phase. The vast majority of the 280 reactions were mild: only one-third required medical treatment. Injected or inhaled adrenaline was applied in six patients. Lüderitz- Püchel et al. calculated the incidence of serious ADRs in this study % per honeybee-venom extract package and % per vespula-venom extract. The American Academy of Allergy, Asthma and Immunology has published a survey on fatal reactions to allergen injections and skin testing (Bernstein et al., 2004). The data are based on a short survey of fatal reactions that had been sent to all American Academy of Allergy, Asthma and Immunology physicians (response: 25%). In addition an 87-item follow-up detailed questionnaire had been sent to those reporting fatal reactions. There were 20 fatal immunotherapy reactions that were directly reported and 21 indirectly reported cases by local physicians. There were 273 (42% of the responding sample) reports of near-fatal reactions. It was estimated that fatal reactions occurred every 1 per injections, with an average of 3.4 deaths per year. Of 17 fatal deaths described in long questionnaires, 15 were in asthmatic patients, the majority of whose symptoms were not optimally controlled. Three reactions occurred in a medically unsupervised setting. Most fatal reactions (59%) occurred with maintenance allergen doses. The authors concluded that fatal reactions to immunotherapy injections occurred at similar rates to those reported in previous surveys. Certain clinical practices have improved (ie exclusion of ß-blockers), and dosing errors were infrequent. Fatal reactions to immunotherapy often occur in settings inappropriate for optimal treatment of anaphylaxis. Strict adherence to practice guidelines might prevent or minimize future fatal reactions. These incorrect techniques are possibly one reason for ADRs which was documented by a survey, endorsed by the American Academy of Allergy, Asthma and Immunology (Aaronson and Gandhi 2004) allergists were asked by whether they knew of an incorrect injection administered within the last 5 years in their offices. 58% of responders reported an event in which a patient had rece- Strona 3

4 Alergologia Współczesna nr 1 (14) ived an injection meant for another patient. 74% of responders reported that patients had received an incorrect amount of vaccine. The effect on patients ranged from local reactions to one fatality. Conclusions Both the American and the German experience for the decade from demonstrate that Specific Immunotherapy is a safe therapy with a low rate of serious adverse effects, although there are many differences in the practice of allergy in these two countries. However, there were some fatalities and a number of serious adverse effects observed. The causes of these events could not be clarified Alergologia Współczesna nr 2 (16) in all cases with precision due to methods of data collection. In addition there may be a considerable number of non-shortcomings in the reported cases. There were nonetheless some similarities between the German and American observations: serious adverse effects including anaphylactic shock may occur during maintenance therapy and later than 30 minutes. Asthma is a risk factor that requires careful attention concerning severity, controller medication and lung function on the day of allergen injection. Adherence to Guidelines is essential in order to minimize adverse effects and at the same time to be prepared for such an event. Long-term efficacy in specific immunotherapy Peter A. Eng Pediatric Pneumonology and Allergology Childrens Hospital, 5000 Aarau, Switzerland Although many studies documented the efficacy of subcutaneous specific immunotherapy (SIT) in patients with seasonal rhinoconjunctivitis, only a few studies exist which deal with long-term efficacy after discontinuation of treatment. In 1988, 28 children (mean age 10.2 years) with severe pollinosis symptoms were recruited for an open controlled study. All patients were mono-sensitized to seasonal allergens and most suffered from seasonal asthma. The patients were assigned to either a three-year course of pre- -seasonal SIT ( ) with grass pollen allergoid (Allergovit ) or symptomatic medication during the pollen season. Patients were followed-up 6 and 12 years after discontinuation of SIT or pharmacological treatment. Twenty-two of the patients were reassessed after 12 years when they were observed prospectively for 14 weeks during the grass pollen season The aim of this follow-up study was to determine whether consistent long- -term benefit could be observed after discontinuation of SIT and how the natural course of the disease had progressed in the two patient groups. Primary endpoint was the symptom medication score during the pollen season. Secondary parameters were skin prick tests with grass pollen allergens, the incidence of new sensitizations to perennial allergens and the course of asthma. The symptom and medication scores correlated with the intensity of the pollination. Total symptom score of the former SIT group (p<0.03) and the combined symptom medication score (p=0.025) were significantly lower than those of the former control group that had used only symptomatic medication. Skin prick testing showed no difference between the groups. New sensitizations to perennial allergens were observed in 100% of the former control group, but in only 58% of the former SIT group (p<0.05). In % of the SIT group and 80% of the control children suffered from pollen associated asthma. 12 years after discontinuation of SIT the figures were 33% and 70% respectively. To our knowledge this is the longest follow-up study after cessation of SIT with inhalant allergens and one of the rare controlled long-term studies in children. It documents the clinical efficacy concerning severity of symptoms and use of anti-allergic drugs during the pollen season even 12 years after discontinuation of SIT. The course of allergic bronchial asthma shows differences in favor of those patients previously treated with immunotherapy. In conclusion, SIT with grass pollen allergoids has not only a specific effect, but also an unspecific influence on the immune system leading to a positive impact on the course of allergic disease. References: 1. Mosbech H., Østerballe O.: Does the effect of immunotherapy last after the termination of treatment? In: Allergy 1988; 43: Jacobsen L., Petersen N.B., Wihl J.Å., Løwenstein H., Ipsen H.: Immunotherapy with partially purified and standardized tree pollen extracts. IV. Results from long-term (6 year) follow-up. In: Allergy 1997; 52: Durham S.R., Walker S.M., Varga E.M., et al.: Long-term clinical efficacy of grass-pollen immunotherapy. New Engl J Med 1999; 341: Eng P.A., Reinhold M., Gnehm H.E.: Long-term efficacy of preseasonal grass-pollen immunotherapy in children. In: Allergy 2002; 57: Strona 4

5 Efficacy and safety of pre-seasonal specific immunotherapy with an aluminium-adsorbed 6-grass pollen allergoid Chris J. Corrigan Guy s, King s and St. Thomas School of Medicine, King s College London for the Study Group* Jens Kettner, Claudia Doemer, Oliver Cromwell, Annemie Narkus Allergopharma Joachim Ganzer KG, Reinbek, Germany Rationale Recent studies suggest that 25 percent of the European population suffers from allergies. Treatment with drugs relieves allergy related symptoms but, with the exception of allergen avoidance, specific immunotherapy (SIT) is the only treatment that can alter the natural history of allergic disease. The introduction of depot preparations, adsorbed to aluminium hydroxide or other adjuvants, has rationalised SIT treatment regimens, allowing fewer injections, while the development of chemically modified allergens (allergoids) has achieved the further goal of producing preparations with a reduced potential for causing immediate hypersensitivity reactions while maintaining immunogenicity. The study compound Allergovit, an aluminium hydroxide adsorbed depot allergoid preparation of 6 grass pollen allergens, was developed as a treatment for short-term preseasonal immunotherapy in seasonal allergic rhinoconjunctivitis. In this study, we investigated the efficacy and safety of Allergovit administered in a pre-seasonal regimen. Methods A 2 year, double-blind, placebo-controlled phase 3 clinical trial was undertaken in 154 patients recruited from allergy clinics in Germany and the UK suffering from symptoms of allergic rhinoconjunctivitis with or without asthma (GINA I or II). Patients were randomised to receive two, pre-seasonal courses of subcutaneous injections of Allergovit or matching placebo given in consecutive years. Two concentrations of Allergovit were used, strength A (1,000 Therapeutic Units [TU]/ml) being a 1:10 dilution of strength B (10,000 TU/ml). All trial preparations were manufactured by Allergopharma Joachim Ganzer KG, Reinbek, Germany. Subcutaneous injections were started in January 2002 at intervals of 7 to 14 days. Doses commenced at 0.1 ml of strength A with an approximate doubling of doses up to 0.6 ml of strength B. The standard regimen comprised of 7 up-dosing injections and a mean of 2 additional maintenance injections prior to onset of the pollen season. During the subsequent pollen seasons, anti-allergic medication on demand was allowed in both treatment groups for symptomatic relief. Symptoms and usage of medication were compared in the specific immunotherapy and the placebo groups. Results A combined symptom and medication score (SMS) was designated as the primary end point for clinical efficacy. The median AUC SMS during the first pollen season following treatment was significantly reduced in the allergoid, as compared with the placebo treated group (median AUC SMS reduction 26.6%, p=0.026) which improved further during the second year (median reduction 48.4%, p=0.018). These differences were apparent during periods of both high and low pollen counts, and irrespective of whether or not the patients also had asthma. With regard to secondary end points, in the second year, the median AUC medication score alone was reduced by 69% in the allergoid, as compared with the placebo treated group. In addition, median Rhinitis Quality of Life scores showed significantly less deterioration (p=0.025) during the pollen season, while allergen tolerance, as judged by a conjunctival provocation test performed after the end of the second pollen season, was very significantly improved (p<0.0001). Highly significant increases in grass pollen allergen-specific IgG 1 and IgG 4 antibody concentrations were measured in association with active treatment. The allergoid was well tolerated: no serous drug related adverse events, including anaphylaxis, were observed in the actively treated group, although as expected there was an increased incidence of minor local and systemic reactions associated with active treatment. Conclusions The grass pollen allergoid was shown to be safe and clinically efficacious in the management of hay fever with or without asthma (GINA I or II). The pre-seasonal regimen is likely to be preferred by patients, and to be more cost effective, especially when set against reductions in conventional therapy. *The Study Group: Dr M Henzgen, Jena; Dr W Feußner, Kassel; Dr R Dominicus, Dülmen; Dr Chr Männer, Arnsberg; Dr D Stiller, Fürstenwalde; Dr S Hofmann, Potsdam; Dr H Scholz, Mahlow; Dr D Futschik, Dresden; Dr C Corrigan, London; Dr K Rajakulasingam, London. Strona 5

6 Clinical efficacy of mite allergoid preparation Anthony J. Frew School of Medicine University of Southampton Mailpoint 810 Southampton General Hospital SO 16 6YD Southampton, GB Current forms of immunotherapy are effective in the treatment of allergic rhinitis and to a lesser extent allergic asthma. However, there are significant concerns regarding the safety of conventional immunotherapy with serious systemic side effects occurring about once in every 500 injections. In addition, the course of treatment is very long and requires specialist supervision. All these factors mean that desensitisation is not as widely used as perhaps it deserves to be. There is now a general consensus that desensitisation works by an effect on T cells that recognise the allergens. Current views suggest that induction of T regulatory cells is the most likely mechanism of benefit. These cells produce interleukin-10 and are associated with the induction of allergen-specific IgG 4 antibodies directed against the allergen. Most of the side effects are thought to be related to IgE antibodies recognising epitopes on the allergen. Since immunotherapy is trying to target the T cell, it should be possible to modify the allergen in such a way that the B cell epitopes are denatured while the T cell epitopes are preserved. A mite allergoid preparation (Acaroid ) is available but has been modified with glutaraldehyde and formaldehyde. Two double-blind placebo-controlled studies have been carried out using this mite allergoid preparation. The first of these was conducted between April 2000 and August 2002 in the UK and Macedonia (Study 97-09) while the second study was conducted between October 2001 and January 2004 as a multi-centre study (Study AI0400av). In both studies the allergoid was given as an increasing dose of 8 injections at intervals of 7-14 days up to a maintenance dose which was then given every 4-6 weeks for a total of 2 years. A total of 215 patients were included in the studies. In common with most allergen immunotherapy studies, the placebo group showed an initial improvement in parallel with the active group but after 12 months, a difference became apparent between the active and placebo groups with a reduction in medication requirements and an improvement in symptom scores. Because the 3 study groups had distinct baseline differences, these effects were checked within a meta-analysis which confirmed a benefit for active treatment at 24 months. Skin test responses to house dust mite were also improved following active treatment (P<0.001). In those patients who exhibited bronchial reactivity, there was a substantial improvement in methacholine provocation tresholds after 12 months and 24 months. The average improvement represented a doubling in the amount of methacholine required to induce a 20% reduction in FEV 1. Allergen-specific IgG 4 increased progressively over the course of the 2 years of treatment in those receiving active therapy whereas there was no change in those on placebo treatment. Local reactions occurred in about 10% of injections and were also seen in those on placebo treatment (13.8%). Systemic symptoms were generally mild and occurred at equal frequency in those on active and placebo therapy. In summary, aldehyde-modified hypo-allergenic allergoids have substantially reduced reactivity to allergen-specific IgE compared with native allergens. These allergoids have been shown in vitro to activate allergen-specific T cells and in vivo to induce the production of allergen-specific IgG 4. These trials with the house dust mite allergoid demonstrate improvement in symptoms and a reduction in the need for rescue medication in patients with perennial rhinitis driven by house dust mite allergy. These improvements in symptom and medication scores are accompanied by a reduction in skin test sensitivity and non-specific bronchial hyper-reactivity. Aldehyde-modified house dust mite allergoids offer valid means to desensitise patients safely and effectively. How efficacious is sublingual therapy? Jörg Kleine-Tebbe, Allergy and Asthma Center Westend, Berlin, Germany Sublingual immunotherapy (SLIT) with inhalant allergens has been increasingly applied in clinical studies for the treatment of individuals with allergic rhinoconjunctivitis and allergic asthma. Most of these studies have been performed in the Mediterranean area, stimulating strong enthusiasm about efficacy and safety of this novel mode of application. On the other side, a number of questions need to Strona 6 be addressed before replacing subcutaneous immunotherapy (SCIT) by the sublingual route for the routine treatment of allergic subjects. Three side by side comparisons of SLIT and SCIT have been published. However, two studies demonstrating equivalent clinical effects of around 50% improvement after immunotherapy regardless of the route of application (1,2) did not use an adequately controlled

7 design. One study in birch pollen allergic patients based on an appropriate double-dummy design (3) demonstrated a 30% change after one year of treatment with SLIT and a 50% change with SCIT compared to placebo with no statistically significant difference between both routes, presumably due to the small number of patients studied. A metaanalysis, comprised of 17 studies in adults and 5 in children with allergic rhinoconjunctivitis, has been published in the Cochrane Library (4), demonstrating an overall modest effect of SLIT in reducing symptom and medication scores compared to placebo treatment. Presentation of subgroup analyses revealed an effect in seasonal allergens (ie grasses), but not in perennial allergens (house dust mite). Adults showed less symptoms and less medication intake after SLIT, but no effect was obtained in children, possibly due to the small number of studies and subjects included. The authors raised following issues in the discussion: 1. What is the ideal dose and treatment duration and is this the same for all allergens, seasonal or perennial? 2. What is the magnitude of symptomatic improvement when SLIT is compared directly with injection immunotherapy? 3. Does SLIT result in modification of the immune response and is the effect of treatment long-lasting, persisting after withdrawal of active treatment? 4. Will compliance with daily home treatment for up to two years be as good outside the confines of a controlled trial? 5. The attractive nature of SLIT as a treatment for children with allergic rhinitis, and also asthma, means that further studies are warranted in this area despite current lack of evidence regarding efficacy. In the meantime, a number of SLIT studies with better design and larger sample sizes have been published with inconsistent or negative results in children. Therefore, SLIT might be used in adults with pollen related rhinoconjunctivitis, particularly if SCIT is not suitable for the patient (ie systemic effects). Fewer data support SLIT for house dust mite allergy or bronchial asthma. Due to a lack of convincing results SLIT for children should only be applied in controlled studies and not in the daily routine. A more substantiated and conclusive judgement of SLIT is possibly warranted in a few years, when more studies with larger patient groups have successfully been published addressing open questions concerning SLIT. References: 1. Quirino T. et al.: Clin Exp Allergy 1996; 26: Mungan D. et al.: Ann Allergy Asthma Immunol 1999; 82: Khinchi MS. et al.: Allergy 2004; 59: Wilson DR. et al.: Sublingual Immunotherapy for allergic rhinitis. Cochrane Database Syst Rev. 2003; (2): CD Reprint in Allergy 2005; 60 (1): 4. The immunopathogenesis of Atopic Dermatitis Mübeccel Akdis Swiss Institute of Allergy and Asthma Research (SIAF), CH-7270 Davos, Switzerland Summary Activated T cells and their products play a major role in the pathogenesis of several skin diseases such as psoriasis and atopic dermatitis (AD). Following activation, selective homing of peripheral-blood T cells, and effector functions in the skin represent sequential immunological events in the pathogenesis. The cutaneous lymphocyte-associated antigen (CLA) represents a homing receptor involved in migration of memory/effector T cells to the skin. CLA is expressed on Th1 cells during the differentiation process and can be induced on Th2 cells by stimulation with bacterial superantigen and/or IL-12. Apparently, skin-selective homing is not restricted to functional and phenotypic T cell subsets. IL-12 and/or superantigen responsiveness such as certain T cell receptor variable β chain expression or IL-12Rβ expression act as factors that control CLA expression on T cells. Both CD4 + and CD8 + T cells bearing CLA represent activated memory/effector T cell subsets in peripheral blood of AD patients. They induce IgE mainly by IL-13 and prolonge eosinophil life span mainly by IL-5. As a mechanism for peripheral Th2 response in atopic diseases, particularly, the Th1 compartment of circulating activated memory/effector T cells selectively undergoes activation-induced cell death, skewing the immune response towards surviving Th2 cells in atopic diseases. A chemokine network involving T cells, dendritic cells and keratinocytes control infiltration of inflammatory cells into AD skin. These activated T cells induce keratinocyte apoptosis via the Fas-dependent pathway representing a key pathogenetic factor in the formation of spongiosis and eczematous lesions. Role of IL-5 and IL-13 in atopic dermatitis Although most patients with AD show high concentrations of total and allergen-specific IgE in blood and skin, some of them express normal IgE levels and show no allergen-specific IgE antibodies. The diagnostic criteria of AD by Hanifin and Rajka can be fulfilled also in the absence of elevated total IgE and specific IgE to food or environmental allergens. This suggests that elevated IgE levels and IgE sensitization are not prerequisites in the pathogenesis of the disease. The subgroup of AD patients with normal IgE levels and without specific IgE sensitization has been Strona 7

8 termed the non-allergic form of AD (NAD), non-atopic eczema, non-ad or intrinsic-type AD. Recent data suggest that T cells are likely to be involved in the pathogenesis of AD and NAD. CD4 + and CD8 + subsets of skininfiltrating T cells as well as skin-homing CLA+ T cells from peripheral blood, equally responded to superantigen, SEB, and produce IL-2, IL-5, IL-13 and IFN-γ in both forms of the disease. Interestingly, skin T cells from AD patients express higher IL-5 and IL-13 levels compared to NAD patients. Thus, T cells isolated from skin biopsies of AD, but not from the NAD, induced high IgE production in cocultures with normal B cells that is mediated by IL-13. In addition, B cell activation with high CD23 expression is observed in the peripheral blood of AD, but not NAD patients. These findings suggest a lack of IL-13-induced B cell activation and consequent IgE production in non-atopic eczema, although high numbers of T cells are present in lesional skin of both types. More importantly, IL-4 and IL-13 neutralization in B cell cocultures with peripheral blood CLA+ skin-homing T cells or skin-infiltrating T cells demonstrated that IL-13 represents the major cytokine for induction of hyper-ige production in AD. Cytokine determinations from peripheral blood CLA + T cells and skin biopsies of AD patients show increased IL-5 expression. Accordingly, supernatants from CLA + T cells of both CD4 + and CD8 + subsets extend the life span of freshly purified eosinophils in vitro, whereas supernatants of CLA - T cells do not influence eosinophil survival. Neutralization of cytokines demonstrated the predominant role of IL-5 secreted from CLA + T cells in prolonged eosinophil survival in AD. Increased activation-induced cell death in Th1 cells as a mechanism of peripheral T helper 2 dominance in atopy It has been proposed that differential organ-specific trafficking of CD4 + Th1 and Th2 cells promote different inflammatory reactions. The great majority of T cells homing to skin are of the CD45RO + memory/effector phenotype and express the skin-selective homing receptor, cutaneous lymphocyte-associated antigen (CLA). Peripheral blood CLA + memory/effector cells demonstrate typical features of activated T cells. Both CD4 + and CD8 + subsets of freshly isolated CLA + T cells express significantly higher levels of CD25, CD40-ligand and HLA-DR. They show spontaneous proliferation, induce IgE production by B cells and enhance eosinophil survival. A polarized peripheral blood Th2 cytokine pattern was regarded as a specific feature reflecting immune disregulation in atopy. Interestingly, a switch in cytokine profile occurs towards Th0/Th1 after skin-homing of T cells in AD. IFN-γ predominates over IL-4 in chronic skin lesions and older patch test reactions, whereas, IL-5 and IL-13 still remain at high levels. IL-12 and IL-18 produced by keratinocytes and dendritic cells in the microenvironment are likely predominant mediators for the induction of IFNγ in T cells after homing to skin. In addition, most of the Strona 8 T cells found in skin-draining lymphatics, which represent skin-de-homing memory/effector T cells, express CLA and increased levels of IFN-γ. The balance between production and death is important in the control of cell numbers within physiological ranges. Cell accumulation in the tissues may be a consequence of either increased cell production or decreased cell death. Because apoptosis of mature T cells is a powerful mechanism for deleting T cells, it raises the interesting possibility that unequal apoptosis of Th1 and Th2 effector cells may lead to preferential deletion of one subset over another. It has been demonstrated that, a fraction of circulating CLA + CD45RO + T cells show direct evidence for in vivo initiated activation-induced cell death (AICD). Immediately after purification, these cells show active caspase-8 and increased caspase degradation, in contrast to their CLA - counterpart and CLA + T cells of healthy individuals and several non-atopic disorders, such as intrinsic types of asthma and AD, psoriasis, contact dermatitis and bee venom allergy. In addition, AICD of CLA + T cells could be inhibited by caspase cascade inhibition and by blocking Fas / Fas-ligand interaction. Characterization of cytokine profile of T cells, which resist or undergo AICD revealed unequal death in Th1 and Th2 cells. In the absence of survival factors and Fas-pathway inhibitors, a Th2-skewed cytokine profile was observed in CD45RO + T cells as well as CLA + CD45RO + T cell clones. Supporting these findings, high IFN-γ-secreting Th1 cells were shown to be short lived that do not efficiently develop into long term memory Th1 cells in mice. By using in vitro generated Th1 and Th2 cells, it was suggested that unequal susceptibility to AICD may be related to increased expression of a Fas-associated phosphatase, FAP-1 in Th2 cells. In the inflammatory forms of allergic diseases, dermis and submucosa turns into a secondary lymphoid organ-like tissue with migrating T cells and dendritic cells. Tissue infiltration of different types of dendritic cells and increased expression of the high affinity receptor for IgE (FceRI) has been repeatedly reported in AD in comparison to non-atopic form. A prerequisite for chronic inflammations is the prolonged survival of inflammatory cells in the affected organs. Loss of attachment to matrix causes apoptosis in many cell types including T cells. This phenomenon, referred to as anoikis (homelessness), was assumed to prevent cells that have lost contact with their original surroundings, from establishing themselves at inappropriate locations. Inflammatory cells reside in a protein network in the tissues, the ECM, which exerts a profound control over them. T cells infiltrating the AD skin are protected from apoptosis by ECM proteins and cytokines, although they express both Fas and Fas-ligand. The effects of ECM are primarily mediated by integrins that can recognize several ECM proteins; conversely, a single ECM protein can bind to several integrins. Cell adhesion to the ECM has been implicated in protection from apoptosis in anchorage-dependent cell

9 types. Apparently, integrin signaling by ECM represents an important survival signal to T cells, although they do not require anchorage in the tissues. In addition, the common g- chain shared by IL-2, IL-4 and IL-15 receptors as well as all other known T cell growth factor receptors is an essential survival signaling component for T cells. T cells induce epithelial cell activation and apoptosis Eczematous skin lesions with distinct etiology are associated with T cell infiltration in the dermis leading to an interaction between T cells and keratinocytes and marked keratinocyte pathology. Transendothelial migration and influx into skin represent the first phase leading to dermal perivascular infiltration by T cells in AD. Interestingly, a second step of chemotaxis takes place in the migration of T cells closer to and into the epidermis, where they augment T cell-mediated effector functions. It has been demonstrated that IFN-γ is one of the most active cytokines during T cell keratinocyte interaction. IFN-γ upregulates MHC class I molecules and Fas, and induces de novo synthesis of MHC class II molecules on keratinocytes. IFN-γ also induces the expression of several cytokines such as IL- 1α, IL-1 receptor agonist, TNF-a and GM-CSF. By IFN-γ stimulation, chemokines such as IFN-γ inducible protein- 10 (IP-10), monokine induced by γ-ifn (Mig) and IFN-γ inducible α chemoattractant (itac) are strongly upregulated in keratinocytes. These chemokines attract T cells bearing the specific receptor CXCR3, which is highly expressed on T cells isolated from skin biopsies of AD patients. An inflammatory process is associated almost invariably with tissue damage and healing. There is growing evidence to incriminate the epidermis and bronchial epithelium as both target and enhancer of the inflammatory response in asthma and AD. Apoptosis of keratinocytes induced by T cells and mediated by Fas is a crucial event in the formation of eczematous lesions in AD and allergic contact dermatitis. Epithelial cells in eczematous skin express functional Fas as an apoptosis receptor. IFN-γ upregulates Fas and renders keratinocytes susceptible to apoptosis. Moderate to severe epithelial apoptosis was demonstrated to be relevant in vivo using lesional skin biopsies in AD. It has to be noted here that receptor affinity and activation tresholds for IFN-γ and Th2 cytokines IL-4, IL-5 and IL-13 show a significant difference. For example, 1 ng/ml of IFN-γ can induce KC apoptosis, whereas 50 ng/ml of IL-4 and IL-13 are required to induce IgE production by B cells and IL-5 to prolong eosinophil life span in vitro. This suggests that a Th2-like T cell, which produces small quantities of IFN-γ can also induce epithelial cell apoptosis. Apparently, keratinocyte apoptosis leads to spongioform morphology in AD. It seems probable that during the course of eczema, keratinocyte stem cells located directly at the basal membrane are protected from T cell induced apoptosis because of strong antiapoptotic signals from dermal fibrocytes and ECM proteins. Conclusion T cells infiltrating the skin use CLA and other receptors to recognize and cross the endothelium. The AD dermis shows an immunological organ like cellular organization with T cells, dendritic cells, which enables a second step of T cell activation by antigens and superantigens. A second step of chemotaxis inside the dermis of AD lesions takes place after transendothelial migration of the inflammatory cells. By IFN-γ stimulation, chemokines such as IFN-γ inducible protein 10 (IP-10), monokine induced by IFN-γ (Mig) and interferon-γ inducible α chemoattractant (itac) are strongly upregulated in keratinocytes. These chemokines attract T cells bearing the specific receptor CXCR3, which is highly expressed on T cells isolated from skin biopsies of AD patients. T cells infiltrating the skin show decreased apoptosis, because they are protected from apoptosis by cytokines and ECM proteins in the dermis. IL-2, IL-4, IL-15 are survival factors for T cells, IL-5, for eosinophils. T cells play an essential role in the induction of keratinocyte apoptosis. IFN-γ, Fas-ligand and TNF-α were identified as inducers of apoptosis. Particularly, the Th1 compartment of circulating activated memory/effector T cells selectively undergoes activation-induced cell death, skewing the immune response towards surviving Th2 cells in atopic diseases. Th2 cells secrete high levels of IL-5 and IL-13 and therefore are capable of prolonging eosinophil life span, inducing IgE production and upregulating homing ligands such as VCAM-1. Future studies to find out novel treatment ways of AD should be focused on inhibition of various modes of T cell activation, inhibition of skin-homing and modulation of effector molecules that play a role in dysregulated apoptosis/survival of T cells, eosinophils and keratinocytes. References: 1. Akdis M., Akdis CA., Weigl L., Disch R., Blaser K.: Skin-homing, CLA+ memory T cells are activated in atopic dermatitis and regulate IgE by an IL-13-dominated cytokine pattern. IgG4 counter-regulation by CLA- memory T cells. J. Immunol. 1997; 159: Akdis M., Simon H-U., Weigl L., Kreyden O., Blaser K., Akdis CA.: Skin homing (Cutaneous Lymphocyte-Associated Antigen-positive) CD8+ T cells respond to superantigen and contribute to eosinophilia and IgE production in atopic dermatitis. J Immunol 1999; 163: Trautmann A., Akdis M., Kleeman D., Altznauer F., Simon H-U., Graeve T., Noll M., Blaser K., Akdis CA.: T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J Clin Invest 2000; 106: Akdis CA., Akdis M., Trautmann A., Blaser K.: Immune regulation in atopic dermatitis. Curr Opin Immunol 2000; 12: Trautmann A., Akdis M., Bröcker E-B., Blaser K., Akdis CA.: New insights into the role of T cells in atopic dermatitis and allergic contact dermatitis. Trends in Immunology 2001; 22: Trautmann A., Schmid-Grendelmeier P., Krüger K., Crameri R., Akdis M., Akkaya A., Bröcker E-B., Blaser K., Akdis CA.: T cells and eosinophils cooperate in the induction of bronchial epithelial apoptosis in asthma. J Allergy Clin Immunol 2002; 109: Akdis M., Trautmann A., Blaser K., Akdis CA.: T cells and effector mechanisms in the pathogenesis of atopic dermatitis. Curr Allergy Asthma Rep. 2002; 2: Akdis M., Trautmann A., Klunker S., Daigle I., Kücüksezer UC., Deglmann W. et al.: T helper (Th) 2 predominance in atopic disease is due to preferential apoptosis of circulating memory/effector Th1 cells. Faseb J. 2003; 17: Akdis CA., Blaser K., Akdis M.: Apoptosis in tissue inflammation and allergic disease. Curr Opin Immunol. 2004; 16 (6): Strona 9

10 Specific immunotherapy in atopic dermatitis General considerations Ulf Darsow, Johannes Ring Division of Environmental Dermatology and Allergy GSF/TUM and Dept. of Dermatology and Allergy Biederstein, Technical University Munich, Germany In patients with atopic eczema (AE), IgE-mediated sensitisations are frequently diagnosed. Aeroallergens are relevant eliciting factors of respiratory atopic diseases, but also of AE. The use of allergen-specific hyposensitization / immunotherapy (SIT) is still controversial in patients with AE, but refined diagnostic methods to characterize subgroups of patients with relevant allergies and the results of several pilot studies give rise to new approaches. Transient deterioration of the eczema, but also clinical improvement was described with SIT in AE. Own experience in a pair of monozygotic twins suffering from spring and summer exacerbation of AE treated in a double-blind placebo-controlled trial with grass pollen SIT showed significant improvement and decrease in serum IgE in the patient treated with SIT. In the placebo-controlled trial of Kaufmann and Roth (1974) AE improved in 13 out of 16 verum-treated patients vs. 4 of 10 in the placebo group. Similar results were reported by others, partially using new methods of local immunotherapy. In a 6-year study of 35 consecutive patients under sublingual SIT, 72% remission was reported by Mastrandrea et al. (2000). No serious adverse events occurred in the published studies. SIT may be a possibility for the treatment of AE. Larger clinical studies with appropriate subgroups of patients are necessary to evaluate safety and efficacy. Specific immunotherapy in atopic dermatitis: DBPC study. Wojciech Silny, Magdalena Czarnecka-Operacz Department of Dermatology and Allergic Diseases Diagnostic Center, University of Medical Sciences, Poznań, Poland Specific immunotherapy (SIT) is the only causative method of treatment in case of IgE-mediated allergic disease. There is extensive literature on the use of SIT in the management of respiratory allergies and insect venom hypersensitivity, but a paucity of published data concerning its use as a therapeutic approach in atopic dermatitis (AD). In the Department of Dermatology and Allergic Diseases Diagnostic Center of the University of Medical Sciences in Poznań we have been investigating this problem for many years obtaining very promising results. Therefore as a final step of our project concerning SIT in AD we performed a double - blind placebo - controlled study. We investigated patients with AD and airborne IgE mediated allergy documented on the basis of clinical examinations, skin prick tests (SPT) and allergen specific serum IgE (asige). 20 AD patients (15 females and 5 males) with monovalent airborne allergy (house dust mite or grass pollen) aged from 5 to 40 years were selected for the study. Recruitment of the patients was very difficult and lasted for 18 months. The allergy vaccines were prepared by Nexter-Allergopharma (Katowice, Poland and Reinbek, Germany) which also sponsored the study. This company was also responsible for both coding and decoding of medications. All allergy vaccinations were decoded after 12 months of SIT when results of allergological and clinical evaluations were completed and transferred to Germany. After receiving the telephone message about the status of vaccinations (active or Figure 1. Mean values of W-AZS in the SIT and placebo groups before and after 12 months of treatment before treatment after treatment SIT group Placebo group placebo) in case of an active medication patients were continuing treatment and in case of placebo group the vaccina- Strona 10

11 tions were started from the initial concentration. Clinical severity of AD was evaluated in accordance with the W-AZS index. Allergological examinations consisted of skin prick tests (Nexter-Allergopharma), evaluation of serum total and specific IgE (Dermatophagoides pteronyssinus, Dermatophagoides farinae, rye-grass, cultivated rye and velvet grass) and ECP (FEIA CAP Pharmacia Diagnostics, Uppsala, Sweden). Remaining immunological parameters were measured before and after 12 months of therapy. Serum concentrations of IL-4, IL-5, IL-10, sil-2r and IFN-γ were measured using commercially available kits in accordance with the manufacturers instructions (ELISA-Quantikine, quantitative colorimetric sandwich ELISA, R&D Systems GmbH, Wiesbaden-Nordenstadt, Germany). Figure 2. Mean serum asige directed against airborne allergens in the SIT and placebo groups before treatment and after 12 months of therapy before treatment after treatmen SIT group Placebo group During the study period (12 months) no systemic treatment was permitted and only topical greasing and moistening agents were used. In case of exacerbations of skin inflammation 0,5% Hydrocortisone cream was permitted for topical treatment. Clinical status of patients was evaluated before and after 12 months of treatment in accordance with the W- AZS index. There was no appreciable difference in severity of disease between the two study groups prior to treatment while after 12 months of treatment the mean value of the W-AZS index decreased significantly from 87.6±15.8 to 38.8±34.4 (-55.7%; p<0.01) in the SIT group, whilst in the placebo group the mean score increased from 86.3±15.7 to 111.9±41.7 (+29.7%; not significant). Comparison of the two groups revealed a statistically significant difference in favour of the active treatment (p<0,01), the score for the SIT group being 65.3% less than that of the placebo group (Figure 1). Clinical efficacy of treatment was also analysed on the basis of the magnitude of the decrease or increase in W-AZS index. Patients receiving active treatment showed clinical improvement in 8 cases (80%), 1 with complete remission, and 2 patients (20%) showed a worsening of their symptoms. In the placebo treated group 9 patients (90%) got worse, and in 1 case (10%) skin inflammation resolved. Concentrations of D. pteronyssinus and D. farinae specific IgE were measured in house dust mite sensitive patients before and after 12 months of immunotherapy. The mean concentration of D. pteronyssinus specific IgE in the active treatment group decreased whilst in the placebo group the concentration increased but in both cases the differences were not statistically significant. Similar changes were also seen in respect of D. farinae as IgE. Grass pollen sensitised patients undergoing active treatment showed two - to three-fold reductions in concentrations of specific IgE reactive with rye-grass, timothy grass, velvet grass and cultivated rye, whereas in the placebo concentrations increased slightly. Considering the global population of patients (house dust mite and grass pollen sensitive cases, n=20) we recorded a significant decrease of specific IgE concentration in the active group (mean value before SIT: 133,3 ±180,6 ku/l; mean value after 12 months of SIT: 70,31 ±106,1 ku/l; p = 0,0002). In case of placebo group the mean concentration of specific IgE before treatment was 61,38 ku/l and increased significantly to 114,0 ku/l after 12 months (p=0,007) (Figure 2). In case of combined population of house dust mite sensitive patients (D. pteronyssinus and D.farinae, n = 14) we observed significant decrease of specific IgE after 12 months of SIT p=0,03 (mean value before SIT: 174,6 ±241,1, mean value after 12 months of SIT: 103,8±137,8). In case of patients treated with placebo vaccinations concentration of asige increased significantly (p=0.04) from 100,90±8,60 ku/l to the value of 192,6±250,6). In the global population of 6 patients sensitive to grass pollen allergens concentration of specific IgE decreased significantly (p=0.002) in the active group (mean concentration before treatment: 85,1±28,2 ku/l, mean value after 12 months of SIT: 31,2±7,2 ku/l). Meanwhile in the placebo group concentration of specific IgE directed against grass pollen allergens increased from 15,3±10,4 ku/l to 22,3±8,0 ku/l, p=0,04. The mean concentration of total IgE remained unchanged after 12 months in the group receiving active treatment while in the placebo group its increase was not significant. The mean serum ECP concentration decreased significantly in the SIT group from 25,1 ±20,3 µg/l at baseline to 10,4 ±8,9 µg/l after 12 months of treatment (p<0,05), whereas a slight increase was recorded in the placebo group. The differences between the two groups were not statistically significant (Figure 3). Selected cytokines and receptors (IFN-γ, sil-2r, IL-4, IL-5, IL-10) were measured in blood sera of patients before treatment and after 12 months of therapy. There were no statistically significant differences between the two study groups in respect of any of the cytokines measured. During our study we did not record any significant adverse events. There were no systemic, anaphylactic reactions observed. Obviously there is a certain possibility of exacer- Strona 11

12 Figure 3. Mean serum level of ECP in AD patients treated with SIT and conventional methods before and after 12 months of therapy before treatment after treatment SIT group Placebo group bation of skin lesions related to allergy vaccinations and we did record 8 such cases of mild and moderate severity during active treatment. We described those cases as possibly related to the treatment and topical corticosteroid therapy was applied. In the control group we also recorded exacerbations possibly related to the treatment (6 cases). They were mild or moderate in severity and required topical antiinflammatory treatment (topical corticotherapy). The results of this study provide adequate justification for us to go ahead with further double blind placebo controlled trials. The results have shown that SIT may be an effective and safe method of treatment for AD patients with IgE-mediated allergies to airborne allergens. We have concluded that this method of treatment is more effective than classical ones, but it should be stressed that careful patient selection is a crucial factor in being able to come to this conclusion. The best results can obviously be expected in cases of monovalent sensitisation and a detailed allergological diagnosis is essential for proper selection of patients and of allergy vaccines. This type of treatment should be systematic and has to be prolonged, possibly for 5 years. Major Allergens or Best Representative Allergens? Adriano Mari Experimental Allergy Unit, IDI-IRCCS, Rome, Italy Keywords Allergy, allergen, sequence, cross-reactivity, co-recognition, IgE. The term major allergen identifies those allergen molecules, which show a positive IgE reactivity in more than 50 % of the subjects in the examined cohort. This is a very practical definition, but sometimes does not properly reflect the nature of allergens as marker of clinical conditions. Studying allergic populations by means of wide panels of allergenic extracts put in evidence the clustering reactivity to certain sources most of the time matching the taxonomical classification of organisms. Furthermore, a certain degree of simplification has been reached for closely related Strona 12 sources by choosing representative extracts giving good results in both diagnosis and immunotherapy of allergic disease (e.g. house dust mites and grasses). Two important findings became evident during the time. The first is that sometimes the in vivo reactivity to taxonomically unrelated allergenic sources clusters in certain allergic patient subsets and the same sources show an unexpected IgE cross-reactivity. This is the case of allergic subjects showing multiple sensitizations within the four main groups of inhalant allergens (arthropods, pollen, mammals and fungi). The second phenomenon is the recorded positivity to certain allergenic sources without prior exposure of the subject. This is the case of taxonomically related organisms living in geographically distant areas or sensitization to foods that have never been eaten before. Since the discovery of immunoglobulin E and the availability of new biochemical and immunochemical tools the approach to the identification of the real IgE binding structure has changed the course of the established source-based approach. The allergenic nature of an increasing number of proteins has been described, and the majority of them are now available as recombinant forms. Biochemical, immunochemical and diagnostic studies are now leading to a reassessment of the clustering in vivo reactivity on a molecular basis. The popular term cross-reactivity derives from the assumption that the sensitizing source is known. It defines

13 the relationship between allergenic sources. This concept mainly considers the allergens and their extracts as the center of the phenomenon. Combining what we know from the allergenic molecule approach and the immunological mechanisms leading to IgE production, the term cross-reactivity does not correctly define both the immunological and the clinical phenomena of allergic sensitization. The term co-recognition could be the best descriptor. The IgE co-recognition of an epitope present on allergens leads to a defined clinical picture, depending on which sources produce the allergen. Several studies support this new concept. Grass pollen allergy is a worldwide seasonal pollinosis. Hundreds of grass species grow in almost all geographical areas of the world. There is a clustering of the reactivity of grass allergic subjects to almost all the extracts they are tested to. The clustering reactivity is easily explained by the close similarity among allergens in grass pollen species. For instance, allergens belonging to the group 1 (ie Lol p 1, Poa p 1, Phl p 1, Dac g 1) have a sequence homology greater then 85% and they are all corecognized by IgE from grass allergic subjects. Some tropical species, like Cynodon dactylon, slightly differ in their IgE reactivity mainly because they don t express some allergens (group 2 and group 5) in their pollen. Several groups of grass allergens have been described so far (groups 1, 2, 4, 5, 11, 13). Studies dealing with IgE reactivity to molecules from each group showed how one of them bears all epitopes present in all the others. This would simplify the molecular approach to immunotherapy for grass pollen allergy. Two interesting natural model of allergen IgE corecognition are sensitizations to group 1 allergens of the Oleaceae family, and group 1 allergens of the Fagales order. Data from the CREATE project showed us that subjects not exposed to olive pollen in England and to birch pollen in Italy, react to Ole e 1, the major allergen from olive pollen, and to Bet v 1, the major allergen from birch, respectively. IgE sensitization to these allergens is acquired by allergic subjects by exposure to related species, ash for olive (Fra e 1 is closely related to Ole e 1), and hazel, oak, chestnut for birch (Cor a 1, Que a 1, Cas s 1 are related to Bet v 1). The IgE co-recognition of epitopes that are common in related species leads to IgE binding to allergen molecules to which the allergic subject is not exposed. In both model, the use of best representative allergens in the Oleaceae family and in the Fagales order may lead to the use of the best representative allergen in each group in immunotherapy regardless of the actual exposure to the molecule source. The last natural model, useful to explain the IgE co-recognition concept and how it leads to the choice of the best representative allergen, is the multiple pollen sensitization syndrome. The spreading of IgE reactivity to most, if not all the pollen species recorded in 18% of the pollen allergic subjects, is due to the reactivity of the so called panallergens. The main feature of this molecule is to be highly conserved structure expressed by organism in almost every cell. IgE produced against these molecules recognize epitopes on any of them regardless the subject is exposed or not. Among pollen allergens, two allergen groups have been studied in deep until now: plant profilins and calcium-binding proteins. Profilins as allergens from plant tissues is the most numerous group of described allergens as of September Eightyfive molecules have been classified from unrelated species, not only from pollen, but also from fruits. This IgE co-recognition explain the clinical picture of these patients having a reactivity to almost all the pollens, earlier appearance of symptoms, and in most of the cases an oral allergy syndrome to many fresh fruits. Plant calcium-binding proteins as allergens account for a minor number of sensitized subjects. Nevertheless the clinical picture is characterized by a strong reactivity to all the pollen species accounting most of the time for severe asthma symptoms. Compared to profilin-sensitized subjects, this subset lacks food allergy as this molecule is not expressed in edible parts of plants. Testing allergic subjects with several profilins or calciumbinding proteins leads to positive results to almost all the tested molecules. In fact, a high degree of co-recognition among homologous panallergens has been described so far. Although considered minor allergens in term of prevalence they show different clinical pictures. A representative molecule might lead to diagnosis and immunotherapy even for these two groups of allergens. The natural models reported above are only few of those that time by time are described in the scientific literature. The careful description of clinical clustering of patients on the basis of their IgE co-recognition of allergenic molecules will help us re-assessing patients allergic phenotypes and the definition of the best representative molecule for each group. This will allow us to define a panel of molecules to be spotted on biochip surfaces for microarray-based IgE diagnosis. Their use in terms of diagnosis and epidemiology will favor the use of allergen molecules for specific immunotherapy. Strona 13

14 References 1. Andersson K., Lidholm J.: Characteristics and Immunobiology of Grass Pollen Allergens. Int Arch Allergy Immunol 2003; 130 (2): Ferreira F., Hawranek T., Gruber P., Wopfner N., Mari A.: Allergic cross-reactivity: from gene to the clinic. Allergy 2004; 59 (3): Mari A., Wallner M., Ferreira F.: Fagales pollen sensitization in a birch-free area: a respiratory cohort survey using Fagales pollen extracts and birch recombinant allergens (rbet v 1, rbet v 2, rbet v 4). Clin Exp Allergy 2003; 33 (10): Mari A.: Multiple pollen sensitization: a molecular approach to the diagnosis. Int Arch Allergy Immunol 2001; 125 (1): Harwanegg C., Laffer S., Hiller R., Mueller MW., Kraft D., Spitzauer S. et al.: Microarrayed recombinant allergens for diagnosis of allergy. Clin Exp Allergy 2003; 33 (1): Niederberger V., Horak F., Vrtala S., Spitzauer S., Krauth MT., Valent P. et al.: Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc. Natl. Acad. Sci USA 2004; 101 (2): Suck R., Hagen S., Cromwell O., Fiebig H.: The high molecular mass allergen fraction of timothy grass pollen (Phleum pratense) between kda is comprised of two major allergens: Phl p 4 and Phl p 13. Clin. Exp. Allergy 2000; 30 (10): Suck R., Nandy A., Weber B., Stock M., Fiebig H., Cromwell O.: Rapid method for arrayed investigation of IgE-reactivity profiles using natural and recombinant allergens. Allergy 2002; 57 (9): van Ree R.: The CREATE project: EU support for the improvement of allergen standardization in Europe. Allergy 2004; 59 (6): Web-sites: Allergen Nomenclature. International Union of Immunological Societies Allergen Nomenclature Sub-Committee. Allergome. A database of allergenic molecules. Potential benefits of recombinant allergens Oliver Cromwell Allergopharma Joachim Ganzer KG, Reinbek, Germany Strona 14 The specific diagnosis and causal treatment of IgE-mediated allergic diseases has relied traditionally on the use of aqueous extracts of various allergenic source materials. The majority of such extracts are complex mixtures of proteins, only some of which exhibit allergenic characteristics. In the cases of two of the most commonly encountered causes of allergic responses, namely grass pollen and the house dust mite Dermatophagoides pteronyssinus, at least 11 and 16 allergens respectively have been identified and characterised. Different allergic patients exhibit different patterns of allergen recognition, and whilst in some cases only one or two allergens may be implicated with an allergic sensitisation in others a whole spectrum of proteins may be involved. Attempts are often made to define the relative importance of allergens in terms of the frequency with which sensitisation can be identified in populations of allergic patients. So called major allergens have traditionally been defined as those which can be associated with sensitisation in more than 50 % of subjects showing reactivity to the allergenic source material and conversely minor allergens are reactive in relatively few subjects. It is the major allergens that are the focus of attention in the development of recombinant molecules since these are the ligands for a large proportion of the allergen specific IgE antibodies that trigger allergic reactions. The quality of an allergen extract is dependent to a large degree on the natural source material from which it is derived, and therefore batch consistency should be controlled as closely as possible. Climatic conditions can influence the relative amounts of proteins in pollens, whilst culture conditions and the methods of harvesting may effect the allergen content of mite and mould extracts. The extraction and purification processes used in extract production are relatively simple, but they have to be conducted under highly reproducible conditions in order to ensure reproducibility. The demonstration of consistent protein patterns and IgE-reactive allergens, together with quantification of individual allergens and measurement of total IgEreactivity, represent important aspects of the characterisation and standardisation of the extracts. The production of proteins by the use of recombinant DNA technology depends initially on the creation of a master cell bank that is the starting point for all routine production batches. The preparation of the cell bank requires that the gene encoding the protein is first isolated; copies of the gene are produced and incorporated into an appropriately designed DNA-expression vector derived from the host cell chosen for expression and production of the protein; and finally the DNA-construct is incorporated into the host cell, typically a bacteria or yeast strain. Each production run starts with an aliquot of cells derived from the one cell bank thus ensuring that the identical protein is always produced. Following a fermentation process the protein is recovered from the cell culture and purified using appropriate chromatographic methods. The end result is a highly purified single protein of pharmaceutical quality that can be easily characterised. The recombinant allergens can be used to formulate optimal preparations for both diagnostic applications and specific causal immunotherapy. The so-called wild type recombinant allergens, exhibiting IgE-reactivity comparable with that of the natural allergens, are particularly suitable for diagnostic applications, but they may also substitute for natural allergens used in specific immunotherapy. Hypoallergenic derivatives have a reduced risk for inducing anaphylactic responses, but can be designed so that they retain T cell reactivity, comparable with that of the native allergens, and thus their therapeutic potential. Traditionally they have been derived by chemical modification of the allergen extracts, but the advent of DNA technology has provided the opportunity to create derivatives by either choosing conditions for expression and/or subsequent folding of the protein that favour an unnatural stable 3-dimensional structure with lower IgE-reac-

15 tivity or using various genetic engineering strategies. Such methods include the introduction of point or deletion mutations by site-directed mutagenesis; the expression of allergen fragments or oligomeric forms; peptide shuffling to produce mosaic molecules; and the creation of molecular hybrids containing portions of two or more different allergens (Ferreira et al, 2002). In a few cases an allergen extract contains one dominant major allergen, possibly together with a few apparently much less important allergens. Good examples are the cat, in which the allergen Fel d 1 is predominant, and birch pollen with the major allergen Bet v 1. In such cases it is realistic to expect that specific immunotherapy based on a single protein will produce a substantial clinical benefit for the patients. The position can be more complicated with some other allergens. Subjects sensitised to pollen from Phleum pratense (Timothy grass), which is representative of grasses found in temperate regions, react predominantly with the two allergens Phl p 1 and Phl p 5, but there are at least a further nine allergens that assume different degrees of importance. Similarly, at least 16 allergens have been characterised from the house dust mite Dermatophagoides pteronyssinus, but the group 1 and 2 allergens are of predominant importance. In these cases it is anticipated that it will be necessary to formulate a mixture of several allergens in order to achieve clinical benefit from specific immunotherapy. However one of the advantages of using recombinant proteins is that the composition of the mixture can easily be optimised to achieve maximum efficacy. The use of recombinant allergens and their derivatives has further advantages in as far as non-allergenic proteins are excluded; the possible risk of contamination by allergens from other sources is avoided; and there is no risk of introducing infectious agents from natural source materials. References: 1. Cromwell O., Suck R., Kahlert H., Nandy A., Weber B., Fiebig H.: Transition of recombinant allergens from bench to clinical application. Methods 2004; 32: Ferreira F., Wallner M., Breiteneder H. et al.: Genetic engineering of allergens: future therapeutic products. Int. Arch. Allergy Immunol. 2002; 128: Specific immunotherapy with recombinant grass pollen allergen cocktail Marek Jutel Wroclaw Medical University, Poland Preparations based on whole grass pollen extracts are used successfully for allergen specific immunotherapy. Recombinant DNA technology provides the possibility to create therapeutic vaccines containing only relevant allergenic proteins. Such preparations promise many advantages with respect to pharmaceutical quality, standardisation, dosage formulation etc., but their clinical efficacy has not been investigated previously. Phleum pratense (Timothy grass) is representative of grasses found in temperate regions. The allergens most frequently inducing sensitisation and high specific IgE concentrations are groups 1 and 5, exemplified by Phl p 1 and Phl p 5 of Phleum pratense, with 90% and 65 to 85% sensitisation rates respectively. The Phl p 2 and Phl p 6 allergens are reactive in 40 60% and 60 70% of grass pollen allergic subjects respectively (Andersson and Lidholm, 2003). The five allergens (Phl p 1, 2, 5a, 5b and 6) have been cloned and expressed in E. coli, purified using various chromatographic procedures and adsorbed to aluminium hydroxide. A cocktail was produced with the allergens in approximately equimolar ratios. A double-blind placebo-controlled clinical trial was undertaken with 62 grass pollen allergic patients suffering from rhinoconjunctivitis with or without asthma (Jutel et al, 2005). Subcutaneous injections of increasing concentrations were given at 7-day intervals prior to the pollen season in 2002, starting with 0.02µg total protein, followed by 0.16µg and then doubling to 40µg total protein (0.8ml) such that the maximum dose contained 10µg Phlp1, 5µg Phlp2, 10µg Phlp5a, 10µg Phlp5b and 5 µg Strona 15

16 Phlp6. Maintenance injections were continued until after the subsequent pollen season with a 50% reduction during each pollen season. A Symptom Medication Score was the primary outcome measure to assess efficacy. Subjects kept diaries for 3 months over each pollen season to record nature and severity of eye, nose and chest symptoms, and type and dose of any medication. A validated rhinitis quality of life questionnaire (RQLQ) (Juniper et al, 1991) was a secondary endpoint. Questionnaires were completed every 2 weeks during the pollen season and the questionnaire following the maximum pollen count was used for analysis. Conjunctival provocation tests were performed before therapy (inclusion criterion) and at the end of the study using a standardized 6-grass allergen extract. The concentration was increased in half-log steps starting with 5 BU/ml until a positive reaction was obtained or a maximum concentration of 5,000 BU/ml, equivalent to 0.18µg Group 5 allergen/drop, was reached. Specific IgE, IgG1 and IgG4 antibody responses to a whole grass pollen allergen extract and individual recombinant allergens were also measured. The median cumulative dose was 490µg total protein, or 122.5µg each of Phl p 1, Phl p 5a and Phl p 5b, and 61.25µg of Phl p 2 and Phl p 6. A per protocol analysis included 24 active treatment and 25 placebo patients. A combined symptom-medication-score adopted as primary end-point showed a 39% improvement in the active treatment group relative to placebo (p=0.041). Symptom score alone showed an improvement of 37% (p=0.015). There was also a reduction in the need for medication reflected in a 36.5% lower medication score. The RQLQ registered an overall significant benefit (p=0.024) from active treatment, providing further evidence of clinical efficacy. Significant effects were seen in 5 of 7 domains tested: activities (p=0.040), non-hay-fever symptoms (p=0.032), practical problems (p=0.040), nasal symptoms (p=0.016) and eye symptoms (p=0.007). A conjunctival provocation test showed a favourable trend (p=0.081) with an increase in the treshold dose. Active treatment induced highly significant increases in both IgG1 and IgG4 grass pollen specific antibody concentrations. IgG1 increased approximately 60-fold, peaking during the first 12 months of the study. IgG4 showed a continuing upward trend, achieving an approximately 4000-fold increase by the end of treatment. Specific IgE levels were not significantly different between groups at the beginning of the study, but thereafter the active treatment group showed a downward trend with values significantly less than baseline. Four subjects in each group had no Phl p 5a/b specific IgE prior to the study, but reacted to Phl p 1 and other grass pollen allergens. None of these subjects developed Phl p 5a/b IgE antibodies during the study, although the 4 subjects receiving active treatment developed strong IgG4 and IgG1 Phl p 5a/b responses consistent with induction of a tolerant immune response. Adverse events were seen with 10.4% of injections of active preparation and 5.9% of placebo, mainly as mild local reactions. Only 7 of 731 active treatment injections (0.8%) were associated with systemic reactions including rhinitis and urticaria. Sensitizations to Group 1, 5a and 5b allergens are the most prevalent and potentially most clinically relevant. We have shown that subcutaneous administration of a cocktail containing these and two additional allergens, is sufficient to achieve significant clinical benefit in subjects with hay fever, whilst also being well tolerated. The combined symptom medication score showed a significant clinical improvement of the same order as the mean additional improvement in disease severity above the response to placebo seen in 43 rhinitis studies with 1,120 treated patients (Malling, 2004). Furthermore, improvement compared favourably with results for oral anti-histamines and topical corticosteroids, particularly when taking into account the well recognized placebo effect associated with immunotherapy (Malling, 1998). Specific immunotherapy results in a deviation in the T lymphocyte response and a modified Th2 response. An increase in T regulatory cells contributes to this process, and antibody responses in this study are consistent with production of IL-10 and TGFβ by these cells, which directly favour suppression of IgE production and a simultaneous increase in IgG4 (and IgA) antibodies respectively. A larger study has now been initiated in order to substantiate these findings. References: 1. Andersson K., Lidholm J.: Characteristics and immunobiology of grass pollen allergens. Int.Arch.Allergy Immunol. 2003; 130: Juniper EF., Guyatt GH.: Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991; 21: Jutel M., Jaeger L., Suck R., Meyer H., Fiebig H., Cromwell O.: Allergen-specific immunotherapy with recombinant grass pollen allergens. J Allergy Clin Immunol. 2005; 116: Malling H-J.: Immunotherapy as an effective tool in allergy treatment. Allergy 1998; 53: Malling H-J.: Allergen immunotherapy efficacy in rhinitis and asthma. Allergy Clin Immunol Int. 2004; 16: Strona 16

17 Production and standardisation of mould extracts Frans M. Kniest Allergopharma Joachim Ganzer KG, Reinbek, Germany Fungi/moulds belong neither to the plant nor to the animal kingdom. They differ from plants in so far as they lack chlorophyll and the subsequent ability to perform photosynthesis. They can be distinguished from animals because they have no organ for food uptake. However, moulds are experts in adapting to their environment and can grow on a number of different energy sources by tightly regulating their metabolism expressing only the proteins needed in a certain environment and for a certain condition. They are also able to express a wide range of stress proteins to protect them from extremities (e.g. heat and cold shocks) in their environment. A part of these proteins have allergenic potency. Moulds differ significantly from other allergen sources because of the complexity of their allergenic profiles. Each mould species expresses a wide range of different allergenic molecules. The allergens are functionally very diverse and belong to several different groups of proteins. Most mould allergens are cytoplasm-proteins and some are secreted into the environment. For a long time it has been thought that many allergens can only be found in spores, but evidence of truly spore specific allergens hardly exists. Despite of this, the event of sporulation might be important for the expression of some allergens. For industrial standardised production we need a specialized company with: A. Specific strain from standardised stock cultures/cell bank; B. Standardised facilities; C. Standardised cultivation procedure; D. Standardised harvesting/de-activation/stabilisation methods. Allergopharma obtains raw material from such a specialized company in Sweden (Allergon). At this high-tech facility standardised cultivation methods with a specific CBS-strain under standardised harvesting methods are performed. However, before the material can be used for medicinal products it is and has to be checked by our quality department for its acceptability by means of different standardised and validated methods. After this procedure, the moulds are extracted and processed to test and therapeutic solutions again by validated methods and finally compared to a standard (In House Reference). The aim of extract standardization is to ensure lot-bylot or batch-to-batch consistency of allergen products. Strict adherence to established manufacturing and quality controls for monitoring consistency can reduce product variability and this goal is realistic within a certain company. Consistency between different manufacturing companies, however, does not appear possible. Allergopharma has in total 20 different mould allergen extracts. The leading mould allergen is Alternaria alternata, which is standardised as pricktest-solution in SBE/ml. This represents a mean PNU-concentration of PNU/ml. All other test and therapeutic mould solutions are standardised in PNU s. SIT in mould allergies Piotr Kuna Div. Allergy and Pneumonology, The Medical University of Łódź Specific immunotherapy, which involves the administration of allergen extracts to patients with symptoms of allergic disorder, is the leading therapeutic tool of modern allergology. It has been shown that patients treated with immunotherapy experience reduced allergic symptoms, require less medication, and have improved quality of life. Immunotherapy prevents the progression of allergic rhinitis to asthma. In addition, a number of studies have shown that immunotherapy is effective in improving pulmonary function, and reducing cost of care in patients with asthma, as well as easing the symptoms of allergic conjunctivitis. Airborne fungal spores have been implicated as causative factors in respiratory allergy. Exposure to high atmospheric spore counts and sensitization to specific fungal allergens have been associated with severe asthma, mainly in young adults (1). The prevalence of sensitization to commercially available fungal extracts used for skin prick tests is approximately 3% in epidemiologic studies. Although in selected patients populations the sensitization rate might increase up to 30%. Of the estimated number of more than 1 million of different fungal species, approximately 80 fungi have been connected with respiratory allergy. Diagnosis and specific immunotherapy with fungal extracts is limited by the complex nature and variability of moulds allergens, lack of good quality allergens extracts and small number of clinical trials with these allergens. Mould allergy is difficult to study. Commercial extracts differ considerably in their composition and allergenic potency. Strona 17

18 Indoor and outdoor moulds can be responsible for allergy symptoms, although the highly complex and variable nature of their allergens make them difficult to study. Among the tens of thousands of moulds species that exist, several are important in allergy. These include Alternaria alternata, Cladosporium cladosporioides (and C. herbarum), Penicillium sp., Aspergillus fumigatus, Epicoccum nigrum, Helminthosporium, Bopolaris, and Drechslera. Allergens from fungal mycelia and spores are less known than allergens from pollen, foodstuffs, insects and animal dander. Depending on geographical and climate conditions the incidence of allergy to a single moulds like Alternaria alternata, Cladosporium herbarum and Aspergillus fumigatus may be as low as 1% of all allergic patients. But, for instance, in the south of the USA, allergies to all moulds together may be as high as 30%. It has been well established that clinically most important moulds in respiratory allergy are Alternaria alternata and Cladosporium. Major allergenic fractions of the two most important mould species have been identified. Standardized extracts of these fungi are available. Resano and Oehling (2) determined the prevalence of airborne moulds sensitization and the reliability of the in vitro diagnostic techniques. They performed a 3-year study in patients diagnosed with rhinosinusitis and/ or bronchial asthma and found moulds sensitization in 101 patients, 20% of whom presented monosensitization against airborne moulds. The most common moulds allergen were Alternaria and Cladosporium. Seventy-six percent of patients had sensitization against Alternaria, 56% of whom were monosensitized, 26% presented cosensitization to Cladosporium and the remainder were sensitive to more than two moulds. Regarding Cladosporium, the percentage of patients was similar (66%), although only 23% were monosensitized and 46% presented an associated sensitization against Alternaria. They also observed a correlation between skin tests and both in vitro diagnostic techniques, with a relative sensitivity of the specific IgE determination compared to the skin test of 98% against Alternaria and 90.4% against Cladosporium, whereas the relative sensitivity of the histamine release test was 97.4% for Alternaria and 85% for Cladosporium. In study performed in children Tariq and coworkers (3) on the group of 1218 children born on the Isle of Wight, and followed for atopy at age 4 years, 981 were skin-prick tested with a battery of allergens. Of these 61 (6%) reacted positively to Alternaria alternata and Cladosporium herbarum (47 to Alternaria, 21 to Cladosporium and seven to both). Twenty-four (39%) were asymptomatic. Asthma References: Strona 18 Alergologia Współczesna nr 2 (16) was the most common disease in children sensitized to moulds. At 4 years of age Alternaria and Cladosporium were the third most common causes of sensitization, ie after house dust mite and grass pollen. Cantani and Ciaschi (4) studied 6840 children with asthma or allergic rhinitis to determine the prevalence of allergy to Alternaria alternata. Diagnosis was established by family and personal history, physical examination, skin prick tests (SPTs) and RAST. Among the 6840 children 213 were positive to Alternaria alternata (3.3%), only 89/6840 children (1.3%) had Alternaria alternata monosensitization. Concerning the clinical manifestations, 83 had asthma or allergic rhinitis, and 6 had asthma associated with atopic dermatitis. Family history was positive in 82.9% of children. The mean onset of AA sensitivity was at age 4 for males, and at age 5 for females. Although immunotherapy with moulds extracts has been performed for many years, the final demonstration of its clinical efficacy is still to be shown. Studies of immunotherapy with moulds allergens are scarce. There are only few studies with Alternaria alternata and Cladosporium published in peer review journals. In recent review on immunotherapy in fungal allergy Helbling and Reimers (5) reported that clinical efficacy of specific immunotherapy with fungal extracts has been shown in 79 actively treated patients in four controlled trials, with only two fungal species, Alternaria alternata and Cladosporium. Horst and coworkers (6) demonstrated that patients only sensitized to Alternaria alternata benefit from specific immunotherapy with standardized Alternaria alternata extracts. Important issue ought to be remembered: specific immunotherapy is ineffective with nonstandardized moulds extracts. There are only two standardized mould allergen extracts - of Alternaria alternata and Cladosporium. Commonly mixtures of allergen extracts are often used for allergy immunotherapy. It is not recommended to mix fungal extracts with pollen extracts. When mould allergens are combined with birch or timothy grass pollen extracts, there is a strong decrease in overall allergenic potency that represented the rapid and complete degradation of some allergens, whereas others remained unaffected. This could result in loss of efficacy, as well as danger of systemic reactions. Immunotherapy with a standardized Alternaria alternata and Cladosporium extracts based on the available data is safe. In the future development and use of recombinant fungal allergens might create new possibilities in diagnosis and specific immunotherapy for fungal allergy. 1. Neukirch C., Henry C., Leynaert B., Liard R., Bousquet J., Neukirch F.: Is sensitization to Alternaria alternata a risk factor for severe asthma? A population based study. J Allergy Clin Immunol 1999; 103: Resano A., Sanz M.L., Oehling A.: Sensitization to Alternaria and Cladosporium in asthmatic patients and its in vitro diagnostic confirmation. J Investig Allergol Clin Immunol 1998; 8: Tariq S.M., Matthews S.M., Stevens M., Hakim F.A.: Sensitization to Alternaria and Cladosporium by the age of 4 years. Clin Exp Allergy 1996; 26: Cantani A., Ciaschi V.: Epidemiology of Alternaria alternata allergy: a prospective study in 6840 Italian asthmatic children. Eur Rev Med. Pharmacol Sci 2004; 8: Helbling A., Reimers A.: Immunotherapy in fungal allergy. Curr Allergy Asthma Rep 2003; 3: Horst, Hejjaoui A., Horst V., Michel FB., Bousquet J.: Double-blind, placebo-controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol 1990; 85:

19 Nasal provocation test in upper airway disease Position statement of the German Society of Allergy and Clinical Immunology (ENT-section) jointly with the Committee of Clinical Immunology, Allergy, and Environmental Medicine of the German Society of Oto- Rhino-Laryngology, Head and Neck Surgery Herbert Riechelmann, Claus Bachert, Oliver Goldschmidt, Bettina Hauswald, Ludger Klimek, Wolfgang W. Schlenter, Abel J. Tasman, Martin Wagenmann Published in German in Allergo J 2002; 11: and Laryngorhinootologie 2003; 82: Translated by Martin Wagenmann, Department of Oto-Rhino-Laryngology, Heinrich-Heine University Düsseldorf Introduction The Guidelines for the execution of nasal provocation tests with allergens for diseases of the upper airways published in 1990 by the Working committee bronchial and nasal provocation tests of the German Society of Allergy and Clinical Immunology set a standard for the diagnostics of allergic diseases in Germany (1). No comparable international guideline exists until now (2-4). An update of the guidelines from 1990 was carried out because additional substances in addition to allergens were introduced for nasal provocation testing, slight modifications in the assessment criteria seemed reasonable, and editorial revisions were necessary. Definition The nasal provocation test (NPT) reproduces the reaction of the nasal mucosa to an inhalable environmental agent under controlled conditions. To this end, the suspected causative agent is brought into contact with the nasal mucosa and the resulting clinical reaction is recorded. In addition to allergens, irritants, drugs and inflammatory mediators can be used for specific problems, e.g. in environmental or occupational medicine. The typical nasal symptoms obstruction, hypersecretion, as well as itching and sneezing are recorded as the response to the exposition. Additionally, ocular, cutaneous, bronchial and systemic reactions are monitored. Changes in nasal patency after the application of allergen are registered utilizing active, anterior rhinomanometry (5 Clinical allergy, nasal allergen provocation). For this purpose the decrease of nasal flow [cm 3 /s] at a transnasal pressure difference of 150 Pa on the initially more patent side of the nose is measured. Only values at inspiration are applied. Background The allergic type-1 reaction of the nasal mucosa is induced by binding of an allergen to specific IgE molecules bound to high-affinity IgE receptors on the surface of mast cells. This leads to degranulation of mast cells in the nasal mucosa and their release of inflammatory mediators. They induce the cardinal symptoms of allergic rhinitis. In the course of this early-phase the released mediators can be detected in nasal secretions (6). Frequently, a biphasic response of the allergic type-1 reaction of the nasal mucosa is observed. The characteristic nasal symptoms can reoccur hours after the initial reaction without repeated allergen exposition (7). They are accompanied by an additional release of cytokines and other mediators (6). This late phase reaction induces a long-lasting cellular inflammatory reaction of the nasal mucosa. It also causes an augmentation of the allergic reaction after further allergen exposition. Repeated intranasal allergen challenge with ragweed pollen lead to an identical response to lower doses of allergen as higher doses in the beginning of these experiments. This finding has been termed nasal priming by Connell (8). During the birch pollen season the treshold concentration to induce a positive NPT according to the guidelines presented here amounts only 10 % of the necessary concentrations, and even 6 weeks after the season 50 % of the pre-seasonal allergen dose suffices to induce a positive response (9). The diagnostics of allergic type-1 diseases relies on history, skin testing, and the determination of allergen specific IgE in the serum. A positive detection of mast cell bound allergen-specific IgE in skin tests or of IgE in the serum is however not equivalent with the evidence of an allergic disease (10). This is confirmed by epidemiological studies in the USA where no correlation between skin test reactivity and chronic rhinitis was found (11), and by a representative Danish study demonstrating positive skin test reactions to house dust mite in 15 % of the population (12) whereas the prevalence of chronic allergic rhinitis in European countries is estimated to be around 2 % (13). In several studies on healthy students without symptoms of allergy positive results of skin prick testing against inhalant allergens were found in % (3, 14, 15). An American study also found no correlation between the concentration of allergen-specific IgE and the severity of symptoms in allergic rhinitis (16). Furthermore, in patients who consulted their physicians due to rhinitic symptoms positive skin test reactions and specific IgE against inhalant allergens were detected, but these allergens could not be related to the patients symptomatology (17-23). It is the goal of nasal provocation tests with allergen to differentiate patients with a clinically relevant sensitization (allergy) against inhalant allergens from patients who are sensitized but fail to develop symptoms under natural allergen exposition (clinically silent sensitization). In individual cases the test is also used to detect nasal reactions to suspected agents despite negative skin tests and negative serological detection of allergen-specific IgE. Allergen-specific Strona 19

20 in pregnancy, in infants, in bad general condition or in testing non-standardized allergen extracts. Technical difficulties may arise due to choanal atresia, septal perforations or nasal polyps. These entities should be excluded before performing NPT by rhinoscopy (if possible using an endoscope). Allergen-solutions and amounts for NPT Isotonic, buffered solutions with neutral ph and with the addition of preservatives are used as testing solutions. Lyophilized allergens are to be restituted following the manufacturers instructions, the date of reconstitution has to written on the label. The allergen solutions have to be stored at 4 C in the refrigerator. Before application the allergen solution has to be brought to room temperature. The storage life of the test solutions has to be shown easily visibly on the bottles. The clinically relevant allergens for each pollen, spores, or animal species have to be contained in reproducible amount and relation within the solutions. The amount of allergen has to be sufficient to induce a clearly detectable reaction in patients with a clinically relevant disease. The allergen concentration within the test solutions of established inhalant allergens has to be biologically standardized. Currently, various Table 1: Commonly used methods for the standardization of allergen solutions Description Unit Definition Histamin Equivalent Potency and related to these Biological Units corresponding to the Nordic Guidelines (27) Optimal diagnostic Concentration (Diagnostic Units) (28) HEP/ml BU/ml BE/ml DU/ml 1 HEP induces the same wheal size in skin prick tests of sensitized individuals as 10 mg/ml histamine. 1 HEP = BU/ml Optimization of sensitivity and specificity by testing different concentrations in sensitized and non-sensitized individuals DU/ml is the concentration that allows the best differentiation between sensitized and nonsensitized individuals. Index of Reactivity (29) IR/ml 100 IR/ml = concentration that induces a mean wheal diameter of 7 mm in skin prick tests of sensitized individuals. Control with 9 % codeine phosphate. Allergy Unit (30) AU/ml Allergy-Unit, used by the FDA. An extract has AU/ml when its concentration induces an erythema with a sum of 50 mm of its horizontal and vertical dimensions IgE can be locally synthesized in the nasal mucosa (24, 25). Therefore it is conceivable that nasal allergy can occur without detectable skin reactions or specific IgE in the serum. In these rare cases the detection of allergies can only be substantiated through nasal allergen provocation (26). Indications and Contraindications An NPT with inhalant allergens is indicated after taking the medical history, skin prick testing, and eventually after the determination of allergen-specific serum IgE, if: the preceding diagnostic procedures didn t give concordant results but the clarification of the clinical significance of the allergen in question is of therapeutic relevance; a sensitization against inhalant allergens has been demonstrated, but the quality of the medical history doesn t allow clinical conclusions; this is e.g. the case in perennial rhinitis where in addition to allergens several non allergic factors could be relevant for the characteristics of the clinical picture; sensitizations against several seasonal allergens exist and their temporal attribution to the symptoms is impossible due to overlap in pollination; the relevance of occupational allergens has to be determined in the case of reeducation or the composition of a medical opinion; in the exceptional case of extranasal manifestations of allergic diseases induced by inhalant allergens; in cases where the clinical picture should be reproduced and where specific IgE can t be detected. Contraindications for the nasal provocation test include: acute inflammatory diseases of the nose or the paranasal sinuses; acute allergic reactions of the immediate type at other organs; severe general conditions; the use of drugs that could augment the risk of intolerances or that could interfere with the treatment of such reactions (such as ACE-inhibitors or beta-blocking agents); vaccinations within the preceding week before the NPT. Particular precaution has to be taken in presumed high degree of sensitization, in poorly controlled bronchial asthma, approaches for the biological standardization are used which leads to difficulties comparing the allergen concentrations used by different manufacturers (Table 1). Standardization for weight/volume, Noon-units, or PNU is no longer appropriate. Standardization for µg major allergen/ml, which is recommended by the WHO, should be implemented rapidly. In the NPT µl of the test solution are applied as spray or drops into one nostril. Prick-test solutions are inappropriate for use in nasal provocation testing since they very frequently contain glycerin that can induce local irritation. After a negative result of the NPT and continuing clinical suspicion of a nasal allergy against a perennial allergen, testing should be repeated with the allergen concentration of the prick test solution. If the test turns out negative again, the reactivity of the nasal mucosa can be tested using 50 µl of a histamine dihydrochloride solution (4 mg/ml) in Strona 20

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