RESUMO
BACKGROUND: Immunotherapy with peptide hydrolysates from Lolium perenne (LPP) is an alternative treatment for seasonal allergic rhinitis with or without asthma. The aim of this study was to assess the clinical efficacy and safety of a cumulative dose of 170 µg LPP administered subcutaneously over 3 weeks. METHODS: In a randomized, double-blind, placebo-controlled trial, 554 adults with grass pollen rhinoconjunctivitis were randomized (1:2 ratio) to receive 8 subcutaneous injections of placebo or 170 µg LPP administered in increasing doses in 4 visits over 3 weeks. The primary outcome was the combined symptom and medication score (CSMS) measured over the peak pollen season. Reactivity to conjunctival provocation test (CPT) and quality of life (QOL) was assessed as secondary endpoints. RESULTS: The mean reduction in CSMS in the LPP vs placebo group was -15.5% (P = .041) during the peak period and -17.9% (P = .029) over the entire pollen season. LPP-treated group had a reduced reactivity to CPT (P < .001) and, during the pollen season, a lower rhinoconjunctivitis QOL global score (P = .005) compared with placebo group. Mostly mild and WAO grade 1 early systemic reaction (ESR) were observed ≤30 minutes in 10.5% of LPP-treated patients, whereas 3 patients with a medical history of asthma (<1%) experienced a serious ESR that resolved with rescue medication. CONCLUSION: Lolium perenne pollen peptides administered over 3 weeks before the grass pollen season significantly reduced seasonal symptoms and was generally safe and well-tolerated.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Asma/terapia , Dessensibilização Imunológica , Peptídeos/imunologia , Poaceae/efeitos adversos , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/terapia , Alérgenos/administração & dosagem , Asma/complicações , Estudos de Casos e Controles , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Esquema de Medicação , Feminino , Humanos , Masculino , Peptídeos/administração & dosagem , Pólen/imunologia , Qualidade de Vida , Rinite Alérgica Sazonal/complicações , Estações do Ano , Resultado do TratamentoRESUMO
BACKGROUND: A novel subcutaneous allergen immunotherapy formulation (gpASIT+™) containing Lolium perenne peptides (LPP) and having a short up-dosing phase has been developed to treat grass pollen-induced seasonal allergic rhinoconjunctivitis. We investigated peptide immunotherapy containing the hydrolysate from perennial ryegrass allergens for the optimum dose in terms of clinical efficacy, immunogenicity and safety. METHODS: This prospective, double-blind, placebo-controlled, phase IIb, parallel, four-arm, dose-finding study randomized 198 grass pollen-allergic adults to receive placebo or cumulative doses of 70, 170 or 370 µg LPP. All patients received weekly subcutaneous injections, with the active treatment groups reaching assigned doses within 2, 3 and 4 weeks, respectively. Efficacy was assessed by comparing conjunctival provocation test (CPT) reactions at baseline, after 4 weeks and after completion. Grass pollen-specific immunoglobulins were analysed before and after treatment. RESULTS: Conjunctival provocation test (CPT) response thresholds improved from baseline to V7 by at least one concentration step in 51.2% (170 µg; P = .023), 46.3% (370 µg), and 38.6% (70 µg) of patients receiving LPP vs 25.6% of patients receiving placebo (modified per-protocol set). Also, 39% of patients in the 170-µg group became nonreactive to CPT vs 18% in the placebo group. Facilitated allergen-binding assays revealed a highly significant (P < .001) dose-dependent reduction in IgE allergen binding across all treatment groups (70 µg: 17.1%; 170 µg: 18.8%; 370 µg: 26.4%). Specific IgG4 levels increased to 1.6-fold (70 µg), 3.1-fold (170 µg) and 3.9-fold (370 µg) (mPP). CONCLUSION: Three-week immunotherapy with 170 µg LPP reduced CPT reactivity significantly and increased protective specific antibodies.
Assuntos
Conjuntivite Alérgica/prevenção & controle , Dessensibilização Imunológica/métodos , Rinite Alérgica Sazonal/prevenção & controle , Adulto , Alérgenos/administração & dosagem , Alérgenos/imunologia , Antígenos de Plantas/administração & dosagem , Antígenos de Plantas/imunologia , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Lolium , Masculino , Peptídeos/administração & dosagem , Peptídeos/imunologiaRESUMO
BACKGROUND: Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short-course treatment with adjuvant-free Lolium perenne peptides (LPP) following a 6-week dose-escalation protocol. METHODS: In a prospective, dose-escalation study, 61 grass pollen-allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG4 and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8). RESULTS: No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became nonreactive to CPT. sIgG4 levels were higher at V6 (8.1-fold, P < .001) and V8 (12.2-fold, P < .001) than at V1. The sIgE:sIgG4 ratio decreased at V6 (-54.6%, P < .001) and V8 (-71.6%, P < .001) compared to V1. The absolute decrease in IgE-facilitated allergen binding was 18% (P < .001) at V6 and 25% (P < .001) at V8. CONCLUSION: Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.
Assuntos
Linfócitos B/imunologia , Dessensibilização Imunológica , Tolerância Imunológica , Lolium/imunologia , Peptídeos/imunologia , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/terapia , Adolescente , Adulto , Alérgenos/imunologia , Linfócitos B/metabolismo , Criança , Pré-Escolar , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Testes de Provocação Nasal , Pólen/imunologia , Rinite Alérgica Sazonal/diagnóstico , Adulto JovemRESUMO
Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.
Assuntos
Conjuntivite Alérgica/prevenção & controle , Dessensibilização Imunológica/métodos , Dessensibilização Imunológica/normas , Rinite Alérgica/prevenção & controle , HumanosRESUMO
This is an updated guideline for the diagnosis and management of allergic and non-allergic rhinitis, first published in 2007. It was produced by the Standards of Care Committee of the British Society of Allergy and Clinical Immunology, using accredited methods. Allergic rhinitis is common and affects 10-15% of children and 26% of adults in the UK, it affects quality of life, school and work attendance, and is a risk factor for development of asthma. Allergic rhinitis is diagnosed by history and examination, supported by specific allergy tests. Topical nasal corticosteroids are the treatment of choice for moderate to severe disease. Combination therapy with intranasal corticosteroid plus intranasal antihistamine is more effective than either alone and provides second line treatment for those with rhinitis poorly controlled on monotherapy. Immunotherapy is highly effective when the specific allergen is the responsible driver for the symptoms. Treatment of rhinitis is associated with benefits for asthma. Non-allergic rhinitis also is a risk factor for the development of asthma and may be eosinophilic and steroid-responsive or neurogenic and non- inflammatory. Non-allergic rhinitis may be a presenting complaint for systemic disorders such as granulomatous or eosinophilic polyangiitis, and sarcoidoisis. Infective rhinitis can be caused by viruses, and less commonly by bacteria, fungi and protozoa.
Assuntos
Rinite Alérgica/diagnóstico , Rinite Alérgica/terapia , Rinite/diagnóstico , Rinite/terapia , Gerenciamento Clínico , Humanos , Rinite/epidemiologia , Rinite/etiologia , Rinite Alérgica/epidemiologia , Rinite Alérgica/etiologiaRESUMO
In this review, we report on relevant current topics in allergen immunotherapy (AIT) which were broadly discussed during the first Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December 2015 by leading clinicians, scientists and industry representatives in the field. The aim of this symposium was to highlight AIT-related aspects of public health, clinical efficacy evaluation, mechanisms, development of new biomarkers and an overview of novel therapeutic approaches. Allergy is a public health issue of high socioeconomic relevance, and development of evidence-based action plans to address allergy as a public health issue ought to be on national and regional agendas. The underlying mechanisms are in the focus of current research that lays the ground for innovative therapies. Standardization and harmonization of clinical endpoints in AIT trials as well as current knowledge about potential biomarkers have substantiated proof of effectiveness of this disease-modifying therapeutic option. Novel treatments such as peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large fraction of patients.
Assuntos
Alérgenos/imunologia , Dessensibilização Imunológica , Hipersensibilidade/imunologia , Hipersensibilidade/terapia , Biomarcadores , Ensaios Clínicos como Assunto , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Gerenciamento Clínico , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/prevenção & controle , Tolerância Imunológica , Resultado do TratamentoRESUMO
BACKGROUND: Clinical efficacy of pollen allergen immunotherapy (AIT) has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time periods predefined based on the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert consensus. METHODS: A Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI reviewed the literature on pollen exposure in the context of defining relevant time intervals for evaluation of efficacy in AIT trials. Underlying principles in measuring pollen exposure and associated methodological problems and limitations were considered to achieve a consensus. RESULTS: The Task Force achieved a comprehensive position in defining pollen exposure times for different pollen types. Definitions are presented for 'pollen season', 'high pollen season' (or 'peak pollen period') and 'high pollen days'. CONCLUSION: This EAACI position paper provides definitions of pollen exposures for different pollen types for use in AIT trials. Their validity as standards remains to be tested in future studies.
Assuntos
Conjuntivite Alérgica/imunologia , Conjuntivite Alérgica/terapia , Dessensibilização Imunológica , Exposição Ambiental/efeitos adversos , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/terapia , Ensaios Clínicos como Assunto , Conjuntivite Alérgica/diagnóstico , Dessensibilização Imunológica/métodos , Relação Dose-Resposta Imunológica , Humanos , Guias de Prática Clínica como Assunto , Rinite Alérgica Sazonal/diagnóstico , Estações do Ano , Avaliação de Sintomas , Fatores de TempoRESUMO
BACKGROUND: Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers. METHOD: The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG-subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE-FAB and IgE-BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?). RESULTS: All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed. CONCLUSIONS: It is recommended to explore the use of allergen-specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE-FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
Assuntos
Asma/diagnóstico , Asma/terapia , Conjuntivite Alérgica/diagnóstico , Conjuntivite Alérgica/terapia , Dessensibilização Imunológica , Rinite Alérgica/diagnóstico , Rinite Alérgica/terapia , Alérgenos/imunologia , Asma/imunologia , Basófilos/imunologia , Basófilos/metabolismo , Biomarcadores , Conjuntivite Alérgica/imunologia , Citocinas/metabolismo , Dessensibilização Imunológica/métodos , Humanos , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Prognóstico , Rinite Alérgica/imunologia , Resultado do TratamentoRESUMO
Rhinitis is a heterogeneous condition that has been associated with inflammatory responses as in allergic rhinitis but can also occur in the absence of inflammation such as in so-called idiopathic (previously 'vasomotor') rhinitis. Allergic rhinitis affects approximately one in four of the population of westernized countries and is characterized by typical symptoms of nasal itching, sneezing, watery discharge and congestion. The intention of this review is to illustrate key concepts of the pathogenesis of rhinitis. Imbalance in innate and adaptive immunity together with environmental factors is likely to play major roles. In allergic rhinitis, initial allergen exposure and sensitization involves antigen-presenting cells, T and B lymphocytes and results in the generation of allergen-specific T cells and allergen-specific IgE antibodies. On re-exposure to relevant allergens, cross-linking of IgE on mast cells results in the release of mediators of hypersensitivity such as histamine and immediate nasal symptoms. Within hours, there is an infiltration by inflammatory cells, particularly Th2 T lymphocytes, eosinophils and basophils into nasal mucosal tissue that results in the late-phase allergic response. Evidence for nasal priming and whether or not remodelling may be a feature of allergic rhinitis will be reviewed. The occurrence of so-called local allergic rhinitis in the absence of systemic IgE will be discussed. Non-allergic (non-IgE-mediated) rhinitis will be considered in the context of inflammatory and non-inflammatory disorders.
Assuntos
Rinite/etiologia , Remodelação das Vias Aéreas , Alérgenos/imunologia , Biomarcadores , Diagnóstico Diferencial , Humanos , Imunoglobulina E/imunologia , Fenótipo , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Rinite/diagnóstico , Rinite/metabolismo , Rinite/terapia , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Rinite Alérgica/metabolismo , Rinite Alérgica/terapiaRESUMO
Follicular helper T cells (Tfh ) are located within germinal centers of lymph nodes. Cognate interaction between Tfh , B cells, and IL-21 drives B cells to proliferate and differentiate into plasma cells thereby leading to antibody production. Tfh cells and IL-21 are involved in infectious and autoimmune diseases, immunodeficiencies, vaccination, and cancer. Human peripheral blood CXCR5(+) CD4(+) T cells comprise different subsets of Tfh -like cells. Despite the importance of the IgE response in the pathogenesis of allergic disorders, little is known about the role of follicular and blood Tfh cells and IL-21 in human and experimental allergic disease. Here, we review recent advances regarding the phenotypic and functional characteristics of both follicular and blood Tfh cells and of the IL-21/IL-21R system in the context of allergic disorders.
Assuntos
Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Fenômenos do Sistema Imunitário , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Imunidade , Interleucinas/metabolismo , Camundongos , Modelos Animais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
BACKGROUND: Specific allergen immunotherapy (SIT) is an effective allergy treatment, but it is unclear whether SIT is effective for atopic eczema (AE). We undertook a systematic review to assess SIT efficacy and safety for treating AE. METHODS: We searched databases, ongoing clinical trials registers, and conference proceedings up to July 2015. Randomized controlled trials (RCTs) of SIT using standardized allergen extracts, compared with placebo/control, for treating AE in patients with allergic sensitization were eligible. RESULTS: We identified 12 eligible trials with 733 participants. Interventions included subcutaneous (six trials), sublingual (four trials), oral or intradermal SIT in children/adults allergic to house dust mite (10 trials), grass pollen or other inhalants. Risk of bias was moderate, with high loss to follow-up and nonblinding as the main concerns. For our primary outcomes, three studies (208 participants) reported no significant difference - patient-reported global disease severity improvement RR 0.75 (95% CI 0.45, 1.26); and eczema symptoms mean difference -0.74 on a 20-point scale (95% CI -1.98, 0.50). Two studies (85 participants) reported a significant difference - SIT improved global disease severity RR 2.85 (95% CI 1.02, 7.96); and itch mean difference -4.20 on a 10-point scale (95% CI -3.69, -4.71). Meta-analysis was limited due to extreme statistical heterogeneity. For some secondary outcomes, meta-analyses showed benefits for SIT, for example investigator-rated improvement in eczema severity RR 1.48 (95% CI 1.16, 1.88; six trials, 262 participants). We found no evidence of adverse effects. The overall quality of evidence was low. CONCLUSION: We found no consistent evidence that SIT is effective for treating AE, but due to the low quality of evidence further research is needed to establish whether SIT has a role in AE treatment.
Assuntos
Dermatite Atópica/terapia , Dessensibilização Imunológica , Eczema/terapia , Alérgenos/imunologia , Terapia Combinada , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Dessensibilização Imunológica/efeitos adversos , Dessensibilização Imunológica/métodos , Eczema/imunologia , Humanos , Viés de Publicação , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: The calcium-binding 2EF-hand protein Phl p 7 from timothy grass pollen is a highly cross-reactive pollen pan-allergen that can induce severe clinical symptoms in allergic patients. Recently, a human monoclonal Phl p 7-specific IgG4 antibody (mAb102.1F10) was isolated from a patient who had received grass pollen-specific immunotherapy (SIT). METHODS: We studied epitope specificity, cross-reactivity, affinity and cross-protection of mAb102.1F10 towards homologous calcium-binding pollen allergens. Sequence comparisons and molecular modelling studies were performed with ClustalW and SPADE, respectively. Surface plasmon resonance measurements were made with purified recombinant allergens. Binding and cross-reactivity of patients' IgE and mAb102.1F10 to calcium-binding allergens and peptides thereof were studied with quantitative RAST-based methods, in ELISA, basophil activation and IgE-facilitated allergen presentation experiments. RESULTS: Allergens from timothy grass (Phl p 7), alder (Aln g 4), birch (Bet v 4), turnip rape (Bra r 1), lamb's quarter (Che a 3) and olive (Ole e 3, Ole e 8) showed high sequence similarity and cross-reacted with allergic patients' IgE. mAb102.1F10 bound the C-terminal portion of Phl p 7 in a calcium-dependent manner. It cross-reacted with high affinity with Ole e 3, whereas binding and affinity to the other allergens were low. mAb102.1F10 showed limited cross-inhibition of patients' IgE binding and basophil activation. Sequence comparison and surface exposure calculations identified three amino acids likely to be responsible for limited cross-reactivity. CONCLUSIONS: Our results demonstrate that a small number of amino acid differences among cross-reactive allergens can reduce the affinity of binding by a SIT-induced IgG and thus limit cross-protection.
Assuntos
Alérgenos/imunologia , Reações Cruzadas/imunologia , Epitopos/imunologia , Imunoglobulina G/imunologia , Imunoterapia , Pólen/imunologia , Alérgenos/química , Sequência de Aminoácidos , Anticorpos Monoclonais/imunologia , Afinidade de Anticorpos/imunologia , Antígenos de Plantas , Cálcio/metabolismo , Epitopos/química , Humanos , Imunoglobulina E/imunologia , Modelos Moleculares , Peptídeos/imunologia , Ligação Proteica/imunologia , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologiaRESUMO
BACKGROUND: Cat allergen is widely distributed in homes and schools; allergic sensitization is common. OBJECTIVE: To develop a model of cat allergen nasal challenge to establish dose-response and time-course characteristics and investigate local and systemic biomarkers of allergic inflammation. METHODS: Nineteen cat-allergic individuals underwent titrated nasal challenge, range 0.243 to 14.6 µg/mL Fel d1, and matched diluent-only provocation. Clinical response to 8 h was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Nasal fluid was collected using polyurethane sponges and analysed by ImmunoCAP and multiplex assays. Whole blood flow cytometry for basophil surface CD63, CD107a, and CD203c was carried out at baseline and 6 h post-challenge. RESULTS: A dose-response to allergen was seen in symptom scores and PNIF, maximal at 10 000 BU/mL (4.87 µg/mL Fel d1), P < 0.0001 vs. diluent. Nasal fluid tryptase was elevated at 5 min after challenge (P < 0.05 vs. diluent); eotaxin, IL-4, -5, -9, and -13 were increased at 8 h (P < 0.05 to P < 0.0001 vs. diluent); TSLP was undetectable; IL-10, IL-17A, and IL-33 were unchanged compared to diluent challenge. Nasal fluid IL-5 and IL-13 correlated inversely with PNIF after challenge (IL-5, r = -0.79, P < 0.0001; IL-13, r = -0.60, P = 0.006). Surface expression of CD63 and CD107a was greater at 6 h than at baseline, both in the presence (both P < 0.05) and absence (CD63, P < 0.01; CD107a, P < 0.05) of in vitro allergen stimulation; no changes were seen on diluent challenge day. CONCLUSIONS: Cat allergen nasal challenge produces local and systemic Th2-driven inflammatory responses and has potential as a surrogate outcome measure in clinical trials.
Assuntos
Alérgenos/imunologia , Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Testes de Provocação Nasal , Adulto , Alérgenos/administração & dosagem , Animais , Basófilos/imunologia , Basófilos/metabolismo , Biomarcadores , Gatos , Citocinas/metabolismo , Feminino , Humanos , Hipersensibilidade/sangue , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Imunofenotipagem , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Testes de Provocação Nasal/métodos , Adulto JovemRESUMO
BACKGROUND: Several studies have demonstrated the time course of inflammatory mediators in nasal fluids following nasal allergen challenge (NAC), whereas the effects of NAC on cells in the periphery are unknown. We examined the time course of effector cell markers (for basophils, dendritic cells and T cells) in peripheral blood after nasal grass pollen allergen challenge. METHODS: Twelve participants with seasonal allergic rhinitis underwent a control (diluent) challenge followed by NAC after an interval of 14 days. Nasal symptoms and peak nasal inspiratory flow (PNIF) were recorded along with peripheral basophil, T-cell and dendritic cell responses (flow cytometry), T-cell proliferative responses (thymidine incorporation), and cytokine expression (FluoroSpot assay). RESULTS: Robust increases in nasal symptoms and decreases in PNIF were observed during the early (0-1 h) response and modest significant changes during the late (1-24 h) response. Sequential peaks in peripheral blood basophil activation markers were observed (CD107a at 3 h, CD63 at 6 h, and CD203c(bright) at 24 h). T effector/memory cells (CD4(+) CD25(lo) ) were increased at 6 h and accompanied by increases in CD80(+) and CD86(+) plasmacytoid dendritic cells (pDCs). Ex vivo grass antigen-driven T-cell proliferative responses and the frequency of IL-4(+) CD4(+) T cells were significantly increased at 6 h after NAC when compared to the control day. CONCLUSION: Basophil, T-cell, and dendritic cell activation increased the frequency of allergen-driven IL-4(+) CD4(+) T cells, and T-cell proliferative responses are detectable in the periphery after NAC. These data confirm systemic cellular activation following a local nasal provocation.
Assuntos
Alérgenos/imunologia , Poaceae/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Adulto , Idoso , Basófilos/imunologia , Basófilos/metabolismo , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-4/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Testes de Provocação Nasal , Testes de Função Respiratória , Rinite Alérgica Sazonal/diagnóstico , Rinite Alérgica Sazonal/metabolismo , Índice de Gravidade de Doença , Testes Cutâneos , Adulto JovemRESUMO
RATIONALE: Nasal allergen provocations may be useful in investigating the pathophysiology of allergic rhinitis and effects of treatments. OBJECTIVE: To use grass pollen nasal allergen challenge (NAC) to investigate the effects of allergen immunotherapy in a cross-sectional study. METHODS: We studied nasal and cutaneous responses in untreated subjects with seasonal grass-pollen allergic rhinitis (n = 14) compared with immunotherapy-treated allergics (n = 14), plus a nonatopic control group (n = 14). Volunteers underwent a standardized NAC with 2000 biological units of timothy grass allergen (equivalent to 1.3 µg major allergen, Phl p5). Nasal fluid was collected and analysed by ImmunoCAP and multiplex assays. Clinical response was assessed by symptom scores and peak nasal inspiratory flow (PNIF). Cutaneous response was measured by intradermal allergen injection. Retrospective seasonal symptom questionnaires were also completed. RESULTS: Immunotherapy-treated patients had lower symptom scores (P = 0.04) and higher PNIF (P = 0.02) after challenge than untreated allergics. They had reduced early (P = 0.0007) and late (P < 0.0001) skin responses, and lower retrospective seasonal symptom scores (P < 0.0001). Compared to untreated allergics, immunotherapy-treated patients had reduced nasal fluid concentrations of IL-4, IL-9 and eotaxin (all P < 0.05, 8 h level and/or area under the curve comparison), and trends for reduced IL-13 (P = 0.07, area under the curve) and early-phase tryptase levels (P = 0.06). CONCLUSIONS: Nasal allergen challenge is sensitive in the detection of clinical and biological effects of allergen immunotherapy and may be a useful surrogate marker of treatment efficacy in future studies.
Assuntos
Citocinas/imunologia , Mucosa Nasal/imunologia , Phleum/imunologia , Extratos Vegetais/uso terapêutico , Pólen/imunologia , Rinite Alérgica Sazonal/tratamento farmacológico , Rinite Alérgica/tratamento farmacológico , Administração Intranasal , Adulto , Secreções Corporais/imunologia , Estudos de Casos e Controles , Estudos Transversais , Dessensibilização Imunológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Nasal/metabolismo , Rinite Alérgica/imunologia , Rinite Alérgica Sazonal/imunologia , Imunoterapia Sublingual , Resultado do Tratamento , Adulto JovemRESUMO
IgG4 purified from patients undergoing specific allergen immunotherapy inhibits the activities of the serum IgE in in vitro assays and is thought to reduce the symptoms of the disease. However, it is not known whether this is related to an intrinsic property of this subclass or only the allergen specificity. We tested the hypothesis that allergen specificity is the critical determinant for this activity using a panel of antibodies with identical specificity but different subclasses. The different antibodies were all able to inhibit the activity of IgE to the same extent. We demonstrate that specificity is the dominant factor determining the ability of an antibody to block allergen-dependent IgE activity.
Assuntos
Anticorpos Bloqueadores/imunologia , Especificidade de Anticorpos/imunologia , Antígenos de Plantas/imunologia , Proteínas de Ligação ao Cálcio/imunologia , Dessensibilização Imunológica , Imunoglobulina A/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Alérgenos/imunologia , Anticorpos Monoclonais , Humanos , Isotipos de Imunoglobulinas/imunologia , Técnicas In VitroRESUMO
BACKGROUND: Within a large prospective study, the Global Asthma and Allergy European Network (GA(2) LEN) has collected skin prick test (SPT) data throughout Europe to make recommendations for SPT in clinical settings. OBJECTIVE: To improve clinical interpretation of SPT results for inhalant allergens by providing quantitative decision points. METHODS: The GA(2) LEN SPT study with 3068 valid data sets was used to investigate the relationship between SPT results and patient-reported clinical relevance for each of the 18 inhalant allergens as well as SPT wheal size and physician-diagnosed allergy (rhinitis, asthma, atopic dermatitis, food allergy). The effects of age, gender, and geographical area on SPT results were assessed. For each allergen, the wheal size in mm with an 80% positive predictive value (PPV) for being clinically relevant was calculated. RESULTS: Depending on the allergen, from 40% (blatella) to 87-89% (grass, mites) of the positive SPT reactions (wheal size ≥ 3 mm) were associated with patient-reported clinical symptoms when exposed to the respective allergen. The risk of allergic symptoms increased significantly with larger wheal sizes for 17 of the 18 allergens tested. Children with positive SPT reactions had a smaller risk of sensitizations being clinically relevant compared with adults. The 80% PPV varied from 3 to 10 mm depending on the allergen. CONCLUSION: These 'reading keys' for 18 inhalant allergens can help interpret SPT results with respect to their clinical significance. A SPT form with the standard allergens including mm decision points for each allergen is offered for clinical use.
Assuntos
Alérgenos/imunologia , Testes Cutâneos/normas , Adolescente , Adulto , Alérgenos/administração & dosagem , Animais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Hipersensibilidade/diagnóstico , Hipersensibilidade/imunologia , Masculino , Pessoa de Meia-Idade , Testes Cutâneos/métodos , Adulto JovemRESUMO
Participant dropouts can reduce the power of allergen immunotherapy clinical trials. Evaluation of the dropout rate and reasons for dropout are important not only in the planning of clinical studies but are also relevant for adherence to immunotherapy in daily clinical practice. A systematic review was carried out in order to establish the overall dropout rate among published double-blind, placebo-controlled randomized clinical trials of sublingual immunotherapy for respiratory allergic diseases. Dropouts were analysed in regards to allergen, formulation, treatment schedule, participant age, study size, number of centres and type of allergic disease. Relative dropout rates in placebo and active groups as well as reasons for dropout were also assessed. A total of 81 studies, comprising 9998 patients, were included. Dropout rates in sublingual immunotherapy controlled studies do not appear to be a major problem with a composite dropout percentage of 14% (95% CI:11.9-16). Furthermore, they are not different for active compared to placebo-treated participants. This lends support to the positive clinical outcomes seen in meta-analyses of these trials.
Assuntos
Ensaios Clínicos como Assunto , Pacientes Desistentes do Tratamento , Imunoterapia Sublingual , Alérgenos , Humanos , RiscoRESUMO
BACKGROUND: The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment. METHODS: The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression. RESULTS: The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2) = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season. CONCLUSIONS: In seasonal allergy trials with grass SLIT-tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results.
Assuntos
Alérgenos/imunologia , Poaceae/efeitos adversos , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual , Adolescente , Adulto , Idoso , Alérgenos/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Estações do Ano , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Allergen immunotherapy (AIT) has been thoroughly documented in randomized controlled trials (RCTs). It is the only immune-modifying and causal treatment available for patients suffering from IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. However, there is a high degree of clinical and methodological heterogeneity among the endpoints in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly accepted standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints. METHODS: As elaborated by a Task Force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group, this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis. RESULTS: Based on a thorough literature review, the TF members have outlined recommendations for nine domains of clinical outcome measures. As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner. All outcomes, grouped into nine domains, are reviewed. CONCLUSION: A standardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required. The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis.