RESUMEN
INTRODUCTION: There is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis. METHODS: Thirty-seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5-grass pollen allergen extracts on aluminium hydroxide (10,000 SQ-U/ml; ALK-Abelló) or placebo using ultrasound-guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen-induced cytokine and chemokine production were analysed using flow cytometry and ELISA. RESULTS: There were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass-induced IFN-γ levels increased only in the actively treated group. CONCLUSION: In this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.
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Rinitis Alérgica Estacional , Humanos , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/terapia , Rinitis Alérgica Estacional/etiología , Betula/efectos adversos , Calidad de Vida , Alérgenos , Polen , Poaceae/efectos adversos , Método Doble Ciego , Inmunoterapia , Extractos Vegetales , Desensibilización Inmunológica/efectos adversosRESUMEN
We investigated the prophylactic and therapeutic effects of the oral administration of transgenic rice seeds expressing a hypoallergenic Bet v 1 derivative of allergic birch pollen conjunctivitis in mice. Transgenic rice seed depositing a chimeric molecule called TPC7 (tree pollen chimera 7) created by DNA shuffling of Bet v 1 family sequences from birch, alder and hazel in protein bodies of endosperm was generated. BALB/c mice were sensitized to birch pollen in alum and challenged with pollen in eyedrops. They were fed TPC7 transgenic or non-transgenic (control) rice seeds for 14 d before sensitization (prophylactic protocol) or 17 d after sensitization (therapeutic protocol). The clinical score and number of conjunctival eosinophils were significantly lower in TPC7-fed mice than in the control mice based on both the prophylactic and therapeutic protocols. Serum concentration of allergen-specific IgE did not differ between TPC7-fed and control groups in either protocol. Prophylactic administration of TPC7 downregulated the production of IL-4 and IFN-γ, whereas therapeutic administration of TPC7 upregulated the production of IFN-γ by allergen-stimulated splenocytes. Prophylactic or therapeutic oral administration of transgenic rice expressing TPC7 suppressed birch pollen-induced allergic conjunctivitis in mice. Feeding transgenic rice is a potentially effective approach as an allergen-specific immunotherapy for allergic conjunctivitis.
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Alérgenos/inmunología , Betula/efectos adversos , Conjuntivitis Alérgica/inmunología , Conjuntivitis Alérgica/prevención & control , Desensibilización Inmunológica , Oryza/genética , Polen/efectos adversos , Vacunas Comestibles/inmunología , Administración Oral , Animales , Conjuntivitis Alérgica/sangre , Inmunoglobulina E/sangre , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Plantas Modificadas Genéticamente , Bazo/patología , Linfocitos T Reguladores/inmunologíaRESUMEN
Subcutaneous immunotherapy (SCIT) is a classic form of allergen-specific immunotherapy that is used to treat birch pollen induced allergic asthma. To investigate the underlying molecular mechanisms of SCIT, we aimed to profile lung samples to explore changes in the differential proteome before and after SCIT in mice with allergic asthma. Fresh lungs were collected from three groups of female BALB/c mice: 1) control mice, 2) birch pollen-induced allergic mice, and 3) birch pollen-induced allergic mice with SCIT. Tandem mass tag (TMT) labelling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to analyze the lung proteome in the mice. Ingenuity pathway analysis (IPA) and Gene Ontology (GO) classification analysis were applied to identify differentially expressed proteins (DEPs) and crucial pathways. The screened DEPs were validated by immunohistochemistry analysis. A total of 317 proteins were upregulated and 184 proteins were downregulated in the asthma group compared to those of the control group. In contrast, 639 DEPs (163 upregulated and 456 downregulated proteins) were identified after SCIT in comparison with those of the asthma group. Among the 639 DEPs, 277 proteins returned to similar levels as those of the relative non-asthma condition. Bioinformatic analysis revealed that the 277 proteins played a significant role in the leukocyte extravasation signaling pathway. The leukocyte extravasation signaling pathway and related DEPs were of crucial importance in birch pollen SCIT.
Asunto(s)
Asma/genética , Desensibilización Inmunológica , Pulmón/metabolismo , Proteoma/genética , Alérgenos/efectos adversos , Alérgenos/inmunología , Animales , Asma/inducido químicamente , Asma/tratamiento farmacológico , Asma/patología , Betula/efectos adversos , Biología Computacional , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Hipersensibilidad/genética , Hipersensibilidad/patología , Infusiones Subcutáneas , Leucocitos/efectos de los fármacos , Leucocitos/inmunología , Pulmón/patología , Ratones , Polen/efectos adversos , Proteoma/efectos de los fármacos , Espectrometría de Masas en TándemRESUMEN
INTRODUCTION: Sublingual immunotherapy (SLIT) with birch pollen extract has been shown to be an efficacious treatment of allergic rhinitis (AR). An as-yet unanswered question is whether and how clinical benefit translates into patient benefit, i.e. what benefit patients derive from this treatment. METHODS: This 1-year, open, prospective, multicenter, non-interventional study conducted in 75 German centers measured patient-relevant benefit of birch pollen SLIT (Staloral® Birch) using the questionnaire "Patient Benefit Index for Allergic Rhinitis (PBI-AR)". At treatment onset, patients rated the importance of 25 treatment needs; after the first birch pollen season on treatment, goal achievement was evaluated. A preference-weighted benefit index was calculated and its association with gender, asthma, allergy status, and severity of AR symptoms was determined. RESULTS: Mean age of the 291 adult patients was 38.8 years; 58.4% were female. The most important treatment goals were to "be able to stay outdoors without symptoms" (87.3% quite or very important), "no longer have a runny or stuffed-up nose" (86.9%), and "be able to breathe through your nose more freely" (86.9%). The treatment goals with the highest benefit ratings (referring to those patients to whom the respective goal applied) were to "have confidence in the therapy" (60.5% has helped "quite" or "very much"), "have an easily applicable treatment" (55.6%), and "be able to breathe through my nose more freely" (51.7%). The average PBI-AR global score was 2.19 (SD 1.04) (0-4; with 4 indicating maximum benefit). No significant differences in PBI-AR global score or subscales were found between men and women, poly- and monoallergic patients, or patients with severe versus mild rhinoconjunctivitis. Patients with asthma reported relevant but lower benefit than patients without asthma. CONCLUSION: After 1 year of birch pollen SLIT treatment, patients reported considerable benefit, mainly due to a reduction of physical symptoms and treatment burden.
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Betula/efectos adversos , Extractos Vegetales/inmunología , Extractos Vegetales/uso terapéutico , Polen/efectos adversos , Polen/inmunología , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/inmunología , Adolescente , Adulto , Anciano , Betula/inmunología , Femenino , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inmunoterapia Sublingual/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Previous clinical trials with birch pollen subcutaneous immunotherapy have been conducted over a 1- to 2-year treatment period and involved mostly a single geographic location. OBJECTIVE: This study (EudraCT-Number: 2005-000025-35) intended to evaluate the effect of subcutaneous immunotherapy with high-dose hypoallergenic birch pollen allergoid in patients with confirmed moderate to severe seasonal allergic rhinitis/rhinoconjunctivitis over a 3-year course in 19 European centres. METHODS: Adults with confirmed birch pollen allergy (n = 253) were randomized to preseasonal placebo (n = 129) or active treatment (n = 124). Primary endpoint was change in Symptom Medication Score after 2 years treatment (2007). RESULTS: The change in Symptom Medication Score of active- vs placebo-treated patients for the Full Analysis Set (n = 227, 15.2% reduction, P = 0.0710) and Per-Protocol Set (n = 216, 16.7% reduction, P = 0.0523) showed a positive trend, although significance was not achieved. The primary endpoint, assessed in 2007, coincided with the lowest pollination during the study period. In a subgroup analysis of patients in the north-eastern region (n = 102), where birch is the major tree and consequently patients' exposure is higher, changes in Symptom Medication Score (32.7% reduction, P = 0.0034) and median number of well days (P = 0.0232) were highly significant in favour of the active group. During the open-label third year of treatment, the mean Symptom Medication Score of active-treated patients was further reduced despite an increased pollen count. Subcutaneous immunotherapy was well tolerated and consistent with the known safety profile. CONCLUSIONS AND CLINICAL RELEVANCE: Although the primary endpoint was not reached for the Full Analysis Set, a significant and clinically relevant effect on Symptom Medication Score was clearly demonstrated for the subgroup of patients in the north-eastern region of Europe, where birch is the predominant tree species. Proving efficacy of birch allergen subcutaneous immunotherapy is challenging due to the numerous factors influencing birch pollen allergen exposure in field studies.
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Alérgenos/inmunología , Betula/efectos adversos , Desensibilización Inmunológica , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/terapia , Adolescente , Adulto , Área Bajo la Curva , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Femenino , Humanos , Inmunoglobulina E/inmunología , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: This randomized, double-blind trial was conducted to determine the optimal dose for clinical efficacy of the SQ tree SLIT-tablet. An environmental exposure chamber (EEC) was used to reduce variability of allergen exposure and allow investigation of symptom reduction towards different species from the birch homologous group in separate EEC sessions. METHODS: Eligible subjects (N = 219) were randomized to receive treatment with placebo or the SQ tree SLIT-tablet (2, 7, or 12 DU) for 24 weeks. EEC pollen challenges were conducted outside the birch pollen season and included four birch and two oak EEC sessions. The primary efficacy endpoint was the average allergic rhinoconjunctivitis (ARC) total symptom score (TSS) after 24 weeks of treatment. RESULTS: There was a statistically significantly lower TSS during the 24-week birch EEC session for 7 DU and 12 DU compared to placebo with relative differences of 24% (P = 0.03) and 25% (P = 0.02). For the 24-week oak EEC session, there was a statistically significant difference for 12 DU (24%, P = 0.03). IgE and IgG4 measurements supported these findings and demonstrated cross-reactivity to all other species within the birch homologous group. Treatment was well-tolerated with the most frequently reported adverse reactions being the local reactions in the oral cavity of mild-to-moderate severity. CONCLUSION: This trial demonstrates that the SQ tree SLIT-tablet reduce ARC symptoms triggered by birch or oak pollen. The optimal dose for further development was 12 DU. Clinical and immunological findings suggest that the tablet may be used to treat allergies to all species within the birch homologous group.
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Betula/efectos adversos , Conjuntivitis Alérgica/inmunología , Inmunoglobulina G/inmunología , Rinitis Alérgica Estacional/inmunología , Inmunoterapia Sublingual , Adolescente , Adulto , Anciano , Conjuntivitis Alérgica/diagnóstico , Femenino , Humanos , Inmunoglobulina E/inmunología , Masculino , Persona de Mediana Edad , Quercus/efectos adversos , Rinitis Alérgica Estacional/diagnóstico , Inmunoterapia Sublingual/efectos adversos , Inmunoterapia Sublingual/métodos , Adulto JovenRESUMEN
BACKGROUND: The underlying mechanism of allergen-specific subcutaneous immunotherapy (SCIT) is not yet fully understood, but suppression of allergen-specific Th2 cells and production of allergen-specific IgG4 antibodies are two hallmarks. The impact on the innate arm of the immune system is far less clear. OBJECTIVE: The aim of this study was to investigate the effect of birch pollen (BP) SCIT on the innate immune response in a BP SCIT mouse model. METHODS: Mice with birch pollen-induced allergic airway inflammation received weekly subcutaneous immunotherapy injections with birch pollen extract (BPE) adsorbed to alum. The effect of the BP SCIT on innate cytokine levels in lung, the number and the functionality of ILC2s and the airway inflammation was determined. RESULTS: Mice with BP allergy had an increased level of the innate cytokines IL-33, IL-25, GM-CSF and IL-5+ ILC2s in the lungs. BP SCIT suppressed the number of IL-5+ ILC2s, mast cell tryptase release, Th2 cytokine production, eosinophil recruitment and peribronchial inflammatory infiltrates. In contrast, innate cytokine production and collagen deposition in the airways were not affected. CONCLUSION AND CLINICAL RELEVANCE: BP SCIT is able to suppress the adaptive and part of the innate immune response, but this is not sufficient to inhibit collagen deposition and the IL-33 expression in the airways in mice.
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Betula/efectos adversos , Desensibilización Inmunológica , Interleucina-33/metabolismo , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/metabolismo , Células Th2/inmunología , Células Th2/metabolismo , Alérgenos/inmunología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/metabolismo , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Modelos Animales de Enfermedad , Femenino , Inmunidad Innata , Pulmón/inmunología , Pulmón/metabolismo , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/terapiaRESUMEN
BACKGROUND: The use of allergen immunotherapy (AIT) for allergic rhinitis and its clinical efficacy in clinical trials depends on the effective determination of pollen allergen exposure time periods. We evaluate pollen data from Germany to examine the new definitions on pollen season and peak pollen period start and end as proposed by the European Academy of Allergy and Clinical Immunology (EAACI) in a recently published Position Paper. The aim was to demonstrate the ability of these definitions to mirror symptom loads for grass and birch pollen-induced allergic rhinitis based on real-life data. METHODS: Data coming from four pollen monitoring stations in the Berlin and Brandenburg area in Germany and for 3 years (2014-2016) were used to investigate the correlation of season definitions, birch and grass pollen counts and total nasal symptom and mediation scores as reported by patients in "Patients Hay fever Diaries" (PHDs). After the identification of pollen periods on the basis of the EACCI criteria, a statistical analysis was employed, followed by a detailed graphical investigation. RESULTS: The analysis revealed that the definitions of pollen season as well as peak pollen period start and end as proposed by the EAACI are correlated to symptom loads for grass and birch pollen-induced allergic rhinitis reported by patients in PHDs. CONCLUSION: Based on our analysis, the validity of the EAACI definitions on pollen season is confirmed. Their use is recommended in future clinical trials on AIT as well as in daily routine for optimal patient care.
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Alérgenos/inmunología , Betula/efectos adversos , Poaceae/efectos adversos , Polen/inmunología , Rinitis Alérgica/diagnóstico , Rinitis Alérgica/inmunología , Manejo de la Enfermedad , Femenino , Geografía , Alemania/epidemiología , Humanos , Masculino , Vigilancia en Salud Pública , Rinitis Alérgica/epidemiología , Rinitis Alérgica/terapia , Estaciones del AñoRESUMEN
BACKGROUND: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. METHODS: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency. RESULTS: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. CONCLUSION: Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.
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Alérgenos/inmunología , Desensibilización Inmunológica , Extractos Vegetales/inmunología , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/terapia , Vacunas/inmunología , Adolescente , Adulto , Alergoides , Austria , Betula/efectos adversos , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Relación Dosis-Respuesta Inmunológica , Esquema de Medicación , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Extractos Vegetales/administración & dosificación , Polonia , Rinitis Alérgica Estacional/diagnóstico , Resultado del Tratamiento , Vacunas/administración & dosificación , Adulto JovenRESUMEN
Birch pollen allergy is diagnosed and treated with aqueous extracts from birch pollen, which contain a mixture of allergens and nonallergenic proteins, including large numbers of closely related sequence variants, so-called iso-allergens of the major allergen, Bet v 1. The quality of therapeutic and diagnostic allergen products largely depends on the allergen and iso-allergen composition. Several biochemical methods are currently applied to detect and quantify allergens and to record protein profiles without differentiating between iso-allergens. Mass spectrometry (MS) may entirely replace these technologies, as it allows sequence specific identification and quantification of proteins and protein profiles including sequence variants in one run. However, the protein inference problem still hampers the automatic assignment of peptide sequences to proteins, consequently impeding the quantification of sequence variants. Therefore, the aim of the study was to set up semitargeted analyses of label-free MS data that allow unambiguous identification and quantification of birch pollen allergens and nonallergenic proteins. We combined data independent acquisition with manual assignment of predefined target sequences for quantification of iso-allergens and automatic quantification of other allergens and nonallergenic proteins. The quantitative data for birch pollen allergens and sequence variants of Bet v 1 were further confirmed by multiple reaction monitoring.
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Antígenos de Plantas/química , Betula/efectos adversos , Hipersensibilidad/diagnóstico , Proteínas de Plantas/química , Alérgenos/efectos adversos , Alérgenos/inmunología , Antígenos de Plantas/inmunología , Betula/química , Betula/inmunología , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Espectrometría de Masas , Proteínas de Plantas/inmunología , Polen/efectos adversos , Polen/inmunología , Control de CalidadRESUMEN
BACKGROUND: Early pollen flight and new allergens prolonging the pollen season means that the time for up-dosing of allergen-specific subcutaneous immunotherapy (SCIT) outside the pollen season becomes shorter. Hence, for patients who wish or need to be up-dosed faster, an accelerated induction regimen would provide a useful treatment option. METHODS: An accelerated up-dosing regimen (0.1-0.3-0.5 mL at weekly intervals) was compared to conventional up-dosing (0.05-0.1-0.2-0.3-0.4-0.5 mL at weekly intervals) using an allergoid birch pollen SCIT preparation. After up-dosing, the maintenance dose (0.5 mL) was given 3 times at biweekly intervals. The multicenter study was performed according to an open randomized, parallel-group design. RESULTS: A total of 123 birch pollen-allergic patients (81 adults and 42 adolescents) presenting with rhinitis or rhinoconjunctivitis with or without mild asthma (FEV1 >70%) were randomized to either the conventional registered up-dosing or an accelerated regimen. In total, 96.7 and 98.4% successfully reached the maintenance dose for the conventional and accelerated regimen, respectively, without relevant differences between adults and adolescents. Both regimens were safe and well tolerated. Furthermore, significant increases (similar in size) in specific IgG and IgG4 after 3 months of treatment were observed in both groups, independent of age. CONCLUSION: The accelerated SCIT regimen was revealed to be as safe as the conventional regimen, and the immunological effects of both regimens are similar. Accordingly, the accelerated regimen may be used to up-dose patients of adult as well adolescent age within 2 weeks.
Asunto(s)
Alérgenos/administración & dosificación , Asma/terapia , Betula/inmunología , Conjuntivitis Alérgica/terapia , Desensibilización Inmunológica/métodos , Rinitis Alérgica Estacional/terapia , Administración Cutánea , Adolescente , Adulto , Alérgenos/efectos adversos , Alérgenos/inmunología , Antígenos de Plantas/efectos adversos , Antígenos de Plantas/inmunología , Asma/inmunología , Betula/efectos adversos , Niño , Conjuntivitis Alérgica/inmunología , Desensibilización Inmunológica/efectos adversos , Femenino , Humanos , Inmunoglobulina E/inmunología , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Polen/efectos adversos , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Adulto JovenRESUMEN
BACKGROUND: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. METHODS: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. RESULTS: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. CONCLUSIONS: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis.
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Alérgenos/inmunología , Antialérgicos/uso terapéutico , Betula/efectos adversos , Conjuntivitis Alérgica/tratamiento farmacológico , Conjuntivitis Alérgica/inmunología , Dibenzazepinas/uso terapéutico , Imidazoles/uso terapéutico , Polen/inmunología , Adulto , Antialérgicos/administración & dosificación , Biomarcadores , Conjuntivitis Alérgica/diagnóstico , Dibenzazepinas/administración & dosificación , Femenino , Histamina/biosíntesis , Humanos , Imidazoles/administración & dosificación , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas , Fenotipo , Lágrimas , Resultado del TratamientoRESUMEN
SCOPE: The BASALIT clinical trial (EudraCT 2009-011737-27) investigated efficacy of birch allergen immunotherapy on lowest observed adverse effect levels after soy food challenge in patients with birch-associated and Gly m 4 allergen mediated soy allergy. Thus, consistently stable Gly m 4 levels were required in standardized challenge meals. METHODS AND RESULTS: Soy meal included soy protein isolate (SPI, 88% total protein). A Gly m 4 specific ELISA was developed and validated. Six SPIs and 24 meal batches were analyzed for Gly m 4. (Repeated-measures) analyses of variance were done to identify potential changes between batches and time intervals. Gly m 4 was below the ELISA detection limit (2 ng/mL) in placebo batches. With <20% mean coefficient of variation, Gly m 4 levels were consistent in 24 soy meal batches and within individual 12-wk shelf-life. CONCLUSION: The novel Gly m 4 specific ELISA proved consistency of challenge meal batches over a 56-month study period. With an average of 178 µg/g Gly m 4 in SPI, Gly m 4 lowest observed adverse effect level can be calculated once clinical lowest observed adverse effect level data based on SPI are available. Hence, sensitivity of patients can be correlated to the relevant allergen content instead of total protein of the allergenic source.
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Antígenos de Plantas/análisis , Ensayo de Inmunoadsorción Enzimática/normas , Análisis de los Alimentos/normas , Antígenos de Plantas/efectos adversos , Antígenos de Plantas/inmunología , Betula/efectos adversos , Betula/inmunología , Ensayos Clínicos como Asunto , Análisis de los Alimentos/métodos , Hipersensibilidad a los Alimentos/inmunología , Almacenamiento de Alimentos , Humanos , Límite de Detección , Estudios Multicéntricos como Asunto , Reproducibilidad de los Resultados , Proteínas de Soja/análisis , Proteínas de Soja/aislamiento & purificaciónRESUMEN
Exhaled breath contains suspended particles of respiratory tract lining fluid from the small airways. The particles are formed when closed airways open during inhalation. We have developed a method called Particles in Exhaled air (PExA® ) to measure and sample these particles in the exhaled aerosol. Here, we use the PExA® method to study the effects of birch pollen exposure on the small airways of individuals with asthma and birch pollen allergy. We hypothesized that birch pollen-induced inflammation could change the concentrations of surfactant protein A and albumin in the respiratory tract lining fluid of the small airways and influence the amount of exhaled particles. The amount of exhaled particles was reduced after birch pollen exposure in subjects with asthma and birch pollen allergy, but no significant effect on the concentrations of surfactant protein A and albumin in exhaled particles was found. The reduction in the number of exhaled particles may be due to inflammation in the small airways, which would reduce their diameter and potentially reduce the number of small airways that open and close during inhalation and exhalation.
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Asma/metabolismo , Pruebas Respiratorias , Espiración , Pulmón/metabolismo , Neumonía/metabolismo , Rinitis Alérgica Estacional/metabolismo , Adulto , Aerosoles , Asma/diagnóstico , Asma/fisiopatología , Betula/efectos adversos , Biomarcadores/metabolismo , Femenino , Humanos , Pulmón/inmunología , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Tamaño de la Partícula , Neumonía/diagnóstico , Neumonía/inmunología , Neumonía/fisiopatología , Polen/efectos adversos , Valor Predictivo de las Pruebas , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/fisiopatología , Albúmina Sérica Humana/metabolismo , Espirometría , Adulto JovenRESUMEN
BACKGROUND: Cross-reactive apple allergy is a common co-morbidity of birch pollen allergy, caused by the presence of a Bet v 1 homologue allergen in apple, Mal d 1. Treatment of tree pollen hay fever by immunotherapy is well established, but its effect on the accompanying apple allergy is debated. OBJECTIVE: To establish a mouse model of birch pollen induced cross-reactivity to Mal d 1 and investigate the effect of birch pollen immunotherapy on the cross-reactivity to Mal d 1. METHODS: Respiratory allergy was induced in Balb/c mice by intraperitoneal exposure to alum-adsorbed birch pollen extract (BPE) in combination with short or prolonged intranasal exposure to BPE. To evaluate the response to Mal d 1, mice were exposed intraperitoneally to Mal d 1. Immunoglobulin responses and cytokine production by splenocytes were measured by ELISA. Allergic symptoms were evaluated by measuring airway hyper-reactivity and hypothermia as a surrogate marker for anaphylaxis. Immunotherapy was performed subcutaneously with alum-adsorbed BPE. RESULTS: Mice exposed to BPE develop cross-reactive IgE to Mal d 1. Early after exposure to BPE, this response is still weak and does not yet translate into anaphylaxis. Interestingly, later re-challenge with BPE increased cross-reactivity to a level where Mal d 1 exposure induced anaphylaxis. Cross-sensitization can also be induced by systemic Mal d 1 exposure. Birch pollen immunotherapy significantly reduced the anaphylactic response of mice to Mal d 1. CONCLUSION & CLINICAL RELEVANCE: A mouse model mimicking birch pollen induced cross-reactivity to Mal d 1 was successfully established. In this model, birch pollen immunotherapy significantly ameliorated the anaphylaxis induced by Mal d 1. Our experimental data suggest that boosting of Mal d 1 recognizing immunoglobulins by BP SCIT is important for the amelioration of apple allergy in human.
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Alérgenos/inmunología , Anafilaxia/inmunología , Antígenos de Plantas/inmunología , Betula/efectos adversos , Reacciones Cruzadas/inmunología , Desensibilización Inmunológica , Malus/efectos adversos , Proteínas de Plantas/inmunología , Polen/inmunología , Anafilaxia/sangre , Animales , Biomarcadores , Modelos Animales de Enfermedad , Femenino , Inmunización , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Terapia de Inmunosupresión , Ratones , Bazo/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
The aim of this study was to investigate voice function in patients with birch pollen allergy. Voice recordings for acoustic analysis were performed during pollen season and non-pollen season, with 30 patients and 30 controls, and all participants answered a questionnaire about voice symptoms. The results show that the patients reported more voice symptoms than controls during both seasons. In the non-pollen season the symptoms were decreased in the patient group but not in the controls. Speaking fundamental frequency was lower in patients compared to controls during both seasons. The results suggest chronic edema of the vocal folds in the patients. Laryngeal examination with stroboscope was not performed but is recommended for future patients diagnosed with an air-borne allergy.
Asunto(s)
Betula/efectos adversos , Polen/efectos adversos , Rinitis Alérgica Estacional/epidemiología , Acústica del Lenguaje , Trastornos de la Voz/epidemiología , Calidad de la Voz , Acústica , Adulto , Betula/inmunología , Estudios de Casos y Controles , Edema/epidemiología , Edema/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polen/inmunología , Prevalencia , Rinitis Alérgica Estacional/diagnóstico , Rinitis Alérgica Estacional/inmunología , Estaciones del Año , Medición de la Producción del Habla , Encuestas y Cuestionarios , Suecia/epidemiología , Factores de Tiempo , Pliegues Vocales/fisiopatología , Trastornos de la Voz/diagnóstico , Trastornos de la Voz/fisiopatologíaRESUMEN
BACKGROUND: Sublingual immunotherapy (SLIT) is a potential efficacious and safe treatment option for patients with respiratory, IgE-mediated allergic diseases. A combined tolerability, dose-finding study with a sublingual liquid birch pollen preparation (SB) was conducted. METHODS: Two hundred and sixty-nine adults with birch-pollen-induced AR were randomized to placebo, SB: 3333, 10,000, 20,000 or 40,000 AUN/ml. Differences in symptom scores following a titrated nasal provocation test (TNPT) at baseline and after 5 months of treatment were determined. Safety, tolerability, birch-pollen-specific immunoglobulin levels and peak nasal inspiratory flow (PNIF) were also measured (all measures determined outside the birch pollen season). RESULTS: In all treatment groups, an improvement in symptom scores after treatment compared to baseline was observed, with an additional stepwise improvement in the active groups compared to placebo, which was significant in high-dose groups (P = 0.008 and P < 0.001, respectively). For this primary endpoint, a significant linear dose-response curve was observed: the higher the dose, the better the improvement observed. Likewise, active treatment resulted in an increase in PNIF and serum IgG levels compared to placebo. The highest improvements were found in the 40,000 AUN/ml group. All active dosages resulted in more adverse reactions than placebo, which were mainly mild and well-controlled. CONCLUSIONS: A multicentre trial evaluated the dose-response and tolerability of SB. All active treatment groups showed better responses than placebo for both primary and secondary parameters. The results indicate that, within the studied dose range, SB 40,000 AUN/ml is the most optimal effective and safe dose (ClinicalTrials.gov: NCT01639768).
Asunto(s)
Alérgenos/inmunología , Betula/efectos adversos , Extractos Vegetales/inmunología , Polen/efectos adversos , Rinitis Alérgica Estacional/inmunología , Rinitis Alérgica Estacional/terapia , Inmunoterapia Sublingual , Adolescente , Adulto , Desensibilización Inmunológica/métodos , Femenino , Humanos , Tolerancia Inmunológica , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Extractos Vegetales/administración & dosificación , Rinitis Alérgica Estacional/diagnóstico , Pruebas Cutáneas , Inmunoterapia Sublingual/efectos adversos , Inmunoterapia Sublingual/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
It is still unclear whether allergen-specific immunotherapy (AIT) with birch pollen improves birch pollen-related food allergy. One reason for this may be the lack of standardized tests to assess clinical reactions to birch pollen-related foods, for example apple. We tested the applicability of recombinant (r) Mal d 1, the Bet v 1-homolog in apple, for oral challenge tests. Increasing concentrations of rMal d 1 in 0.9% NaCl were sublingually administered to 72 birch pollen-allergic patients with apple allergy. The dose of 1.6 µg induced oral allergy syndromes in 26.4%, 3.2 µg in 15.3%, 6.3 µg in 27.8%, 12.5 µg in 8.3%, 25 µg in 11.1%, and 50 µg in 4.2% of the patients. No severe reactions occurred. None of the patients reacted to 0.9% NaCl alone. Sublingual administration of 50 µg of rMal d 1 induced no reactions in three nonallergic individuals. Our approach allows straight forward, dose-defined sublingual challenge tests in a high number of birch pollen-allergic patients that inter alia can be applied to evaluate the therapeutic efficacy of birch pollen AIT on birch pollen-related food allergy.
Asunto(s)
Alérgenos/inmunología , Antígenos de Plantas/inmunología , Betula/efectos adversos , Hipersensibilidad a los Alimentos/diagnóstico , Hipersensibilidad a los Alimentos/inmunología , Malus/efectos adversos , Proteínas de Plantas/inmunología , Polen/inmunología , Rinitis Alérgica Estacional/inmunología , Administración Sublingual , Adulto , Alérgenos/administración & dosificación , Femenino , Hipersensibilidad a los Alimentos/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Rinitis Alérgica Estacional/complicaciones , Adulto JovenRESUMEN
BACKGROUND: Late allergic reactions are common in the course of allergen-specific immunotherapy and even occur with allergy vaccines with reduced IgE reactivity. OBJECTIVE: We sought to study atopy patch test (APT) reactions and T-cell responses to the recombinant birch pollen allergen Bet v 1 and recombinant hypoallergenic T-cell epitope-containing Bet v 1 fragments in patients with birch pollen allergy with and without atopic dermatitis (AD). METHODS: A clinical study was conducted in 15 patients with birch pollen allergy with AD (group 1), 5 patients with birch pollen allergy without AD (group 2), 5 allergic patients without birch pollen allergy (group 3), and 5 nonallergic subjects (group 4) by performing skin prick tests and APTs with rBet v 1 and hypoallergenic rBet v 1 fragments. T-cell, cutaneous lymphocyte antigen (CLA)(+) and CCR4(+) T-cell and cytokine responses were studied by thymidine uptake, carboxyfluorescein diacetate succinimidyl ester staining, and Luminex technology, respectively. RESULTS: rBet v 1 and hypoallergenic rBet v 1 fragments induced APT reactions in not only most of the patients with birch pollen allergy with AD (11/15) but also in most of those without AD (4/5). Patients with birch pollen allergy with AD had higher Bet v 1-specific proliferation of CLA(+) and CCR4(+) T cells compared with patients with birch pollen allergy without AD. There were no differences in Bet v 1-specific CLA(+) and CCR4(+) proliferation and cytokine secretion in patients with and without APT reactions. CONCLUSION: Hypoallergenic rBet v 1 fragments induce T cell-dependent late reactions not only in patients with birch pollen allergy with AD but also in those without AD, which can be determined based on APT results but not based on in vitro parameters.