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‣ Toll-like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin-specific allergic airway disease: role of MyD88 adaptor molecule and interleukin-12/interferon-gamma axis

BORTOLATTO, J.; BORDUCCHI, E.; RODRIGUEZ, D.; KELLER, A. C.; FAQUIM-MAURO, E.; BORTOLUCI, K. R.; MUCIDA, D.; GOMES, E.; CHRIST, A.; SCHNYDER-CANDRIAN, S.; SCHNYDER, B.; RYFFEL, B.; RUSSO, M.
Fonte: WILEY-BLACKWELL Publicador: WILEY-BLACKWELL
Tipo: Artigo de Revista Científica
Português
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Background Epidemiological and experimental data suggest that bacteria] lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll-like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro-Type 1 T helper cells (Th 1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. Objective We determined whether natural (LPS) or synthetic (ER-803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS-induced molecular pathways, we used TLR4-, MyD88-, TRIF-, or IL-12/IFN-gamma-deficient mice. Methods Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co-adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. Results Sensitization with OVA plus LPS co-adsorbed onto alum impaired in dose-dependent manner OVA-induced Th2-mediated allergic responses such as airway eosinophilia...

‣ Enhancement of Th1 Lung Immunity Induced by Recombinant Mycobacterium bovis Bacillus Calmette-Guerin Attenuates Airway Allergic Disease

CHRIST, Ana P.; RODRIGUEZ, Dunia; BORTOLATTO, Juliana; BORDUCCHI, Erica; KELLER, Alexandre; MUCIDA, Daniel; SILVA, Joao S.; LEITE, Luciana C. C.; RUSSO, Momtchilo
Fonte: AMER THORACIC SOC Publicador: AMER THORACIC SOC
Tipo: Artigo de Revista Científica
Português
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Mycobacterium bovis Bacillus Calmette-Guerin (BCG) has been shown to down-regulate experimental allergic asthma, a finding that reinforced the hygiene hypothesis. We have previously found that recombinant BCG (rBCG) strain that express the genetically detoxified Si subunit of pertussis toxin (rBCG-S1PT) exerts an adjuvant effect that enhances Th1 responses against BCG proteins. Here we investigated the effect of this rBCG-S1PT on the classical ovalbumin-induced mouse model of allergic lung disease. We found that rBCG-S1PT was more effective than wild-type BCG in preventing Th2-mediated allergic immune responses. The inhibition of allergic lung disease was not associated with increased concentration of suppressive cytokines or with an increased number of pulmonary regulatory T cells but was positively correlated with the increase in IFN-gamma-producing T cells and T-bet expression in the lung. In addition, an IL-12-dependent mechanism appeared to be important to the inhibition of lung allergic disease. The inhibition of allergic inflammation was found to be restricted to the lung because when allergen challenge was given by the intraperitoneal route, rBCG-S1PT administration failed to inhibit peritoneal allergic inflammation and type 2 cytokine production. Our work offers a nonclassical interpretation for the hygiene hypothesis indicating that attenuation of lung allergy by rBCG could be due to the enhancement of local lung Th1 immunity induced by rBCG-S1PT. Moreover...

‣ Modelo experimental de conjuntivite alérgica crônica em camundongos; Experimental model of chronic allergic conjunctivitis in murines

Machado, Marco Antonio de Campos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 14/09/2005 Português
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INTRODUÇÃO: A conjuntivite alérgica é a forma mais comum de doença alérgica que afeta o olho. Neste trabalho, desenvolvemos um modelo murino reprodutível e simular a doença humana, para possibilitar o estudo dos mecanismos fisiopatológicos da conjuntivite alérgica crônica. MÉTODOS: Imunizamos os camundongos BALB/c e C57Bl/6 com extrato do ácaro Dermatophagoides pteronyssinus (Dpt). Foi realizada a dissecção dos linfonodos ilíacos e para-aórticos, e a enucleação dos olhos. O plasma obtido pela punção cardíaca foi utilizado para a dosagem de IgE e IgG totais e específicas para Dpt. Os olhos enucleados foram enviados para estudo anátomo-patológico da conjuntiva e córnea. RESULTADOS: 1) Houve uma diferença estatisticamente significante entre as duas linhagens (BALB/c e C57Bl/6) para os grupos imunizados com 5 ?g e 500 ?g na gradação clínica e histopatológica, dosagens de IgE Total e Específica, proliferação de linfócitos específica para Dpt e IgG Específica, e na dosagem das IL-5, IL-8 e IL-13; 2) Os níveis de IgG Total não se mostraram significantes para as duas linhagens nos grupos imunizados com 5 ?g e 500 ?g; 3) Os níveis de IL-4 e IL-10 tiveram uma diferença significante nos animais da linhagem BALB/c imunizados com 5 ?g e 500 ?g...

‣ Tregs and allergic disease

Robinson, Douglas S.; Larché, Mark; Durham, Stephen R.
Fonte: American Society for Clinical Investigation Publicador: American Society for Clinical Investigation
Tipo: Artigo de Revista Científica
Publicado em 15/11/2004 Português
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Allergic diseases such as asthma, rhinitis, and eczema are increasing in prevalence and affect up to 15% of populations in Westernized countries. The description of Tregs as T cells that prevent development of autoimmune disease led to considerable interest in whether these Tregs were also normally involved in prevention of sensitization to allergens and whether it might be possible to manipulate Tregs for the therapy of allergic disease. Current data suggest that Th2 responses to allergens are normally suppressed by both CD4+CD25+ Tregs and IL-10 Tregs. Furthermore, suppression by these subsets is decreased in allergic individuals. In animal models, Tregs could be induced by high- or low-dose inhaled antigen, and prior induction of such Tregs prevented subsequent development of allergen sensitization and airway inflammation in inhaled challenge models. For many years, allergen-injection immunotherapy has been used for the therapy of allergic disease, and this treatment may induce IL-10 Tregs, leading to both suppression of Th2 responses and a switch from IgE to IgG4 antibody production. Improvements in allergen immunotherapy, such as peptide therapy, and greater understanding of the biology of Tregs hold great promise for the treatment and prevention of allergic disease.

‣ Th9 and allergic disease

Soroosh, Pejman; Doherty, Taylor A
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /08/2009 Português
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Helper CD4+ T-cell subsets have improved our understanding of adaptive immunity in humans and in animal models of disease. These include T helper type 1 (Th1), Th2 and the interleukin-17 (IL-17) -producing population ‘Th17’. Th2 cells have been described as orchestrating the immune response in allergic disease based on studies with patient samples and animal models. The cytokine IL-9 has largely been regarded as a Th2 cytokine that makes multifocal contributions to allergic disease. Recent data suggest that under certain conditions relevant to chronic disease (IL-4 and transforming growth factor-β), a distinct population of IL-9-producing ‘Th9’ helper T cells can exist. The contribution of Th9 cells in allergic disease is currently unknown, and this review will propose a model for how these cells may regulate chronic allergic inflammation.

‣ CLIMATE CHANGE, AEROALLERGENS AND PEDIATRIC ALLERGIC DISEASE

Sheffield, Perry E.; Weinberger, Kate R.; Kinney, Patrick L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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The degree to which aeroallergens are contributing to the global increase in pediatric allergic disease is incompletely understood. We review the evidence that links climate change to changes in aeroallergens such as pollen and outdoor mold concentrations and subsequently, aeroallergen association with pediatric allergic disease. We specifically explore the evidence on both the exacerbation and the development of allergic disease in children related to outdoor pollen and mold concentrations. Pediatric allergic diseases include atopic dermatitis or eczema, allergic rhinitis or hay fever, and some types of asthma in children, typically defined as less than 18 years of age. We discuss how the timing of aeroallergen exposure both in utero and in childhood could be associated with allergies. We conclude that the magnitude and type of health impacts due to climate change will depend on improved understanding of the relationship between climatic variables, multiple allergen factors, and allergic disease. Improved public health strategies such as adequate humidity control, optimum air filtration and ventilation, and improved anticipatory public health messaging will be critical to adaptation.

‣ The role of epigenetic dysregulation in the epidemic of allergic disease

Prescott, Susan; Saffery, Richard
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
Publicado em 13/04/2011 Português
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The epidemic of allergic disease in early life is one of the clearest indicators that the developing immune system is vulnerable to modern environmental changes. A range of environmental exposures epidemiologically associated with allergic disease have been shown to have effects on the foetal immune function in pregnancy, including microbial burden, dietary changes and environmental pollutants. Preliminary studies now suggest that these early effects on immune development may be mediated epigenetically through a variety of processes that collectively modify gene expression and allergic susceptibility and that these effects are potentially heritable across generations. It is also possible that rising rates of maternal allergy, a recognised direct risk factor for infant allergic disease, may be further amplifying the effects of environmental changes. Whilst effective prevention strategies are the ultimate goal in reversing the allergy epidemic, the specific environmental drivers, target genes, and intracellular pathways and mechanisms of early life immune programming are still unclear. It is hoped that identifying genes that are differentially regulated in association with subsequent allergic disease will assist in identifying causal pathways and upstream contributing environmental factors. In this way...

‣ Probiotic Therapy as a Novel Approach for Allergic Disease

Toh, Zheng Quan; Anzela, Anzela; Tang, Mimi L. K.; Licciardi, Paul V.
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
Publicado em 21/09/2012 Português
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The prevalence of allergic disease has increased dramatically in Western countries over the past few decades. The hygiene hypothesis, whereby reduced exposure to microbial stimuli in early life programs the immune system toward a Th2-type allergic response, is suggested to be a major mechanism to explain this phenomenon in developed populations. Such microbial exposures are recognized to be critical regulators of intestinal microbiota development. Furthermore, intestinal microbiota has an important role in signaling to the developing mucosal immune system. Intestinal dysbiosis has been shown to precede the onset of clinical allergy, possibly through altered immune regulation. Existing treatments for allergic diseases such as eczema, asthma, and food allergy are limited and so the focus has been to identify alternative treatment or preventive strategies. Over the past 10 years, a number of clinical studies have investigated the potential of probiotic bacteria to ameliorate the pathological features of allergic disease. This novel approach has stemmed from numerous data reporting the pleiotropic effects of probiotics that include immunomodulation, restoration of intestinal dysbiosis as well as maintaining epithelial barrier integrity. In this mini-review...

‣ TGFβ Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease

Frischmeyer-Guerrerio, Pamela A.; Guerrerio, Anthony L.; Oswald, Gretchen; Chichester, Kristin; Myers, Loretha; Halushka, Marc K.; Oliva-Hemker, Maria; Wood, Robert A.; Dietz, Harry C.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 24/07/2013 Português
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Transforming growth factor–β (TGFβ) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGFβ regulates regulatory T cell (Treg) maturation and immune homeostasis. Although genetic manipulation of the TGFβ pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGFβ, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in their plasma. They had an increased frequency of CD4+ T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. TH2 cytokine–producing cells accumulated in cultures of naïve CD4+ T cells from LDS subjects, but not controls, after stimulation with TGFβ...

‣ Epigenomics and allergic disease

Lockett, Gabrielle A; Patil, Veeresh K; Soto-Ramírez, Nelís; Ziyab, Ali H; Holloway, John W; Karmaus, Wilfried
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2013 Português
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Allergic disease development is affected by both genes and the environment, and epigenetic mechanisms are hypothesized to mediate these environmental effects. In this article, we discuss the link between the environment, DNA methylation and allergic disease, as well as questions of causality inherent to analyses of DNA methylation. From the practical side, we describe characteristics of allergic phenotypes and contrast different epidemiologic study designs used in epigenetic research. We examine methodological considerations, how best to conduct preprocessing and analysis of DNA methylation data sets, and the latest methods, technologies and discoveries in this rapidly advancing field. DNA methylation and other epigenetic marks are firmly entwined with allergic disease, a link that may hold the basis for future allergic disease diagnosis and treatment.

‣ The Relationship between Interleukin-18 Polymorphisms and Allergic Disease: A Meta-Analysis

Cheng, Daye; Hao, Yiwen; Zhou, Wenling; Ma, Yiran
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
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Recent studies have suggested that IL-18 −607C/A and −137G/C polymorphisms may be associated with the risk of allergic disease; however, individually published results are inconclusive. Therefore, we performed a meta-analysis to clarify whether IL-18 −607C/A and −137G/C polymorphisms were associated with the risk of allergic disease. A total of 21 studies including 5,331 cases and 9,658 controls were involved in this meta-analysis. In the overall analysis and the subgroup analysis according to ethnicity, we did not find significant association between IL-18 −607C/A or −137G/C polymorphism and the risk of allergic disease (all P > 0.05). However, in a stratified analysis by type of allergic disease, our results indicated that IL-18 −607C/A polymorphism was associated with a significantly decreased risk of allergic asthma in heterozygous comparison and IL-18 −137G/C was associated with a significantly decreased risk of allergic dermatitis in recessive model and homozygous comparison. In the stratified analysis by source of control, IL-18−607C/A showed significantly reduced risk in population-based subgroup, and for IL-18 −137G/C only significantly decreased risk was found in the hospital-based subgroup. Our meta-analysis suggests that IL-18 −607C/A and −137G/C polymorphisms may be protective factors for the risk of allergic asthma and allergic dermatitis...

‣ 25-Hydroxyvitamin D, IL-31, and IL-33 in Children with Allergic Disease of the Airways

Bonanno, Anna; Gangemi, Sebastiano; La Grutta, Stefania; Malizia, Velia; Riccobono, Loredana; Colombo, Paolo; Cibella, Fabio; Profita, Mirella
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
Português
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Low vitamin D is involved in allergic asthma and rhinitis. IL-31 and IL-33 correlate with Th2-associated cytokines in allergic disease. We investigated whether low vitamin D is linked with circulating IL-31 and IL-33 in children with allergic disease of the airways. 25-Hydroxyvitamin D [25(OH) Vit D], IL-31, and IL-33 plasma levels were measured in 28 controls (HC), 11 allergic rhinitis (AR) patients, and 35 allergic asthma with rhinitis (AAR) patients. We found significant lower levels of 25(OH) Vit D in AR and in AAR than in HC. IL-31 and IL-33 plasma levels significantly increased in AAR than HC. IL-31 and IL-33 positively correlated in AR and AAR. 25(OH) Vit D deficient AAR had higher levels of blood eosinophils, exacerbations, disease duration, and total IgE than patients with insufficient or sufficient 25(OH) Vit D. In AAR 25(OH) Vit D levels inversely correlated with total allergen sIgE score and total atopy index. IL-31 and IL-33 did not correlate with 25(OH) Vit D in AR and AAR. In conclusion, low levels of 25(OH) Vit D might represent a risk factor for the development of concomitant asthma and rhinitis in children with allergic disease of the airways independently of IL-31/IL-33 Th2 activity.

‣ Genetic risk factors for the development of allergic disease identified by genome-wide association

Portelli, M A; Hodge, E; Sayers, I
Fonte: BlackWell Publishing Ltd Publicador: BlackWell Publishing Ltd
Tipo: Artigo de Revista Científica
Português
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An increasing proportion of the worldwide population is affected by allergic diseases such as allergic rhinitis (AR), atopic dermatitis (AD) and allergic asthma and improved treatment options are needed particularly for severe, refractory disease. Allergic diseases are complex and development involves both environmental and genetic factors. Although the existence of a genetic component for allergy was first described almost 100 years ago, progress in gene identification has been hindered by lack of high throughput technologies to investigate genetic variation in large numbers of subjects. The development of Genome-Wide Association Studies (GWAS), a hypothesis-free method of interrogating large numbers of common variants spanning the entire genome in disease and non-disease subjects has revolutionised our understanding of the genetics of allergic disease. Susceptibility genes for asthma, AR and AD have now been identified with confidence, suggesting there are common and distinct genetic loci associated with these diseases, providing novel insights into potential disease pathways and mechanisms. Genes involved in both adaptive and innate immune mechanisms have been identified, notably including multiple genes involved in epithelial function/secretion...

‣ Vitamin D intake in mid-pregnancy and child allergic disease – a prospective study in 44,825 Danish mother-child pairs

Maslova, Ekaterina; Hansen, Susanne; Jensen, Camilla B; Thorne-Lyman, Andrew L; Strøm, Marin; Olsen, Sjurdur F
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
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Background: Past studies suggest that maternal vitamin D intake during pregnancy may protect against child wheeze but studies on asthma are limited. Our objective was to examine the relation between intake of vitamin D in mid-pregnancy and child asthma and allergic rhinitis at 18 months and 7 years. Methods: We examined data from 44,825 women enrolled during pregnancy in the longitudinal Danish National Birth Cohort (1996–2002). We estimated vitamin D intake from diet and supplements based on information from a validated food frequency questionnaire completed in gestational week 25. At 18 months, we evaluated child asthma using data from phone interviews. We assessed asthma and allergic rhinitis by self-report at age 7 and asthma by using records from national registries. Current asthma at age 7 was defined as lifetime asthma diagnosis and wheeze in the past 12 months. We calculated multivariable risk ratios with 95% CIs comparing highest vs. lowest quintile of vitamin D intake in relation to child allergic disease outcomes. Results: The median (5%-95%ile) intake of total vitamin D was 11.7(3.0-19.4) μg/day (68% from supplements). In multivariable analysis, mothers in the highest (vs. lowest) quintile of total vitamin D intake were less likely to have children classified with current asthma at 7 years (Q5 vs. Q1: 0.74...

‣ Diet of lactating women and allergic reactions in their infants

Palmer, D.; Makrides, M.
Fonte: Lippincott Williams & Wilkins Publicador: Lippincott Williams & Wilkins
Tipo: Artigo de Revista Científica
Publicado em //2006 Português
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PURPOSE OF REVIEW: To evaluate whether the diet of lactating women modulates the development of allergic disease in their children. RECENT FINDINGS: Although maternal avoidance of common food protein allergens was previously recommended for lactating women with infants predisposed to allergic disease, recent expert reviews have concluded that there is no strong evidence to support this position. A recent well-controlled study, using egg as an allergen, confirmed that the appearance of food proteins in human milk is common, but this can be highly variable between women even after consuming the same challenge (dose) food. On the other hand, preliminary data suggest that increasing dietary n-3 fatty acids may offer protection from the development of some childhood allergies. A recent animal study offers mechanistic support, indicating that perinatal diets high in n-3 fatty acids can induce oral neonatal tolerance more effectively compared with diets predominating in n-6 fatty acids. SUMMARY: Current data do not support the use of maternal antigen-avoidance diets during lactation as a strategy to prevent childhood allergies. Controlled trials are required to evaluate the efficacy of maternal dietary n-3 fatty acid interventions in preventing allergic disease in at-risk infants.

‣ Eosinophils promote allergic disease of the lung by regulating CD4+ Th2 lymphocyte function

MacKenzie, J.; Mattes, J.; Dent, L.; Foster, P.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2001 Português
Relevância na Pesquisa
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Eosinophils are primarily thought of as terminal effectors of allergic responses and of parasite elimination. However, limited studies suggest a more discrete immunomodulatory role for this leukocyte during these inflammatory responses. In this investigation, we highlight the potential of eosinophils to act as APCs and thus modulators of allergic responses by influencing Th2 cell function. In response to Ag provocation of the allergic lung, eosinophils rapidly trafficked to sites of Ag deposition (airways lumen) and presentation (lung-associated lymph nodes and T cell-rich paracortical zones). Eosinophils from the allergic lung expressed class II MHC peptides, T cell costimulatory molecules (CD80 and CD86), and rapidly internalized and processed Ag that was sampled from within the airway lumen. Ag-loaded eosinophils promoted the production of IL-4, IL-5, and IL-13 in cocultures with in vitro-polarized Th2 cells and induced IL-5 production in a dose-dependent manner from Ag-specific CD4+ T cells isolated from allergic mice. In addition, Ag-loaded eosinophils primed for Th2 cell-driven allergic disease of the lung when transferred to naive mice. Thus, eosinophils have the potential to not only activate Th2 cells to release disease-modulating cytokines but also to assist in priming the immune system for allergic responses. This investigation highlights the potential of eosinophils to not only act as terminal effector cells but also to actively modulate allergic inflammation by amplifying Th2 cell responses.; Jason R. MacKenzie...

‣ Modulation of Allergic Disease through the use of Th1-associated Vaccine Adjuvants

Johnson-Weaver, Brandi Tranae
Fonte: Universidade Duke Publicador: Universidade Duke
Tipo: Dissertação
Publicado em //2015 Português
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The prevalence of allergic disease such as peanut (PN) allergy has increased within the last century. Environmental factors have been associated with an increased risk of developing allergic diseases. The severity of allergic diseases has also increased and clinical trials are investigating allergen-specific immunotherapy as a method to treat allergies. The purpose of this work was to identify a vaccine adjuvant that induced potent antigen-specific Th1 immune responses and determine its ability to reduce the development and severity of Th2- mediated allergic disease, using models of peanut hypersensitivity.

Three studies were performed. The first study compared a variety of vaccine adjuvants to identify a potent adjuvant with strong Th1-associated activity. This study verified that the Toll-like receptor (TLR) ligand CpG could induce potent Th1-associated immune responses. The second study tested the ability of environmental endotoxin levels and alum-adjuvanted vaccines to modulate the development of allergic disease using a mouse model of peanut allergy. Additionally, the TLR ligands, CpG and MPL, were combined with alum-adjuvanted vaccines to determine their ability to further impact allergic disease development. Results suggested that the addition of CpG to an alum-adjuvanted vaccine indirectly modified host immunity in a manner that decreased the development of PN-induced allergic disease. The last study evaluated the ability of CpG to reduce the severity of peanut allergy symptoms when combined with peanut in an immunotherapy formulation administered to peanut-hypersensitive mice. Nasal immunotherapy with PN + CpG but not PN alone or CpG alone reduced the severity of PN-induced anaphylaxis in hypersensitive mice. PN-hypersensitive mice treated with PN + CpG displayed an increased PN-specific IgG2c and IFN-γ responses. A reduction in allergic disease severity in PN-hypersensitive mice correlated with an increase in PN-specific IgG2c...

‣ Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity

Yang, Ming; Hogan, Simon; Mahalingam, Surendran; Pope, Samuel; Zimmermann, Nives; Fulkerson, Patricia; Dent, Lindsay; Young, Ian; Matthaei, Klaus; Rothenberg, Marc E; Foster, Paul S
Fonte: Mosby Inc Publicador: Mosby Inc
Tipo: Artigo de Revista Científica
Português
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Background: Eotaxin-2 is a member of the eotaxin subfamily of CC chemokines that display eosinophil-specific, chemotactic properties and has been associated with allergic disorders. However, the contribution of eotaxin-2 to the development of defined pathogenic features of allergic disease remains to be defined. Objective: We sought to determine whether eotaxin-2 was a cofactor with IL-5 for the regulation of pulmonary eosinophilia and to identify the combined role of these molecules in the induction of phenotypic characteristics of allergic lung disease. Methods: We instilled recombinant eotaxin-2 into the airways of wild-type mice that had been treated systemically with IL-5 or into IL-5-transgenic mice and characterized pulmonary eosinophil numbers, IL-13 production, and airway hyperreactivity (AHR) to methacholine. Mice deficient in the IL-4 receptor α-chain, IL-13, and signal transducers and activators of transcription 6 or mice treated with anti-CCR3 monoclonal antibody were also used. Results: Eotaxin-2 and IL-5 cooperatively promoted eosinophil accumulation, IL-13 production, and AHR to methacholine. Neither eotaxin-2 nor IL-5 alone induced these features of allergic disease. IL-13 production was critically dependent on eotaxin-2- and IL-5-regulated eosinophilia...

‣ Interleukins-4, -5, and -13: emerging therapeutic targets in allergic disease

Foster, Paul S; Martinez-Moczygemba, Margarita; Huston, David P; Corry, David
Fonte: Pergamon-Elsevier Ltd Publicador: Pergamon-Elsevier Ltd
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
67.50015%
For the first time, allergic diseases have emerged as major public health concerns. Highly effective therapies for allergic disease now exist, but are plagued by serious side effects and the fact that a significant minority of patients remains unresponsive. Studies from many laboratories have established that T helper type 2 (TH2) cytokines contribute importantly to diseases such as asthma, and therapeutic strategies that target the key TH2 cytokines are of potential benefit in allergic disease. In this article, we will review the biology of the TH2 cytokines interleukin (IL)-4, IL-5, and IL-13 and their receptors, and will consider several novel strategies to neutralize these molecules in human and experimental asthma. While promising, newer therapies face a gauntlet of developmental challenges, but offer the hope of reducing allergic diseases once again to minor public health concerns.

‣ Eosinophils promote allergic disease of the lung by regulating CD4(+) Th2 lymphocyte function

Mackenzie, Jason; Mattes, Joerg; Dent, Lindsay; Foster, Paul S
Fonte: American Association of Immunologists Publicador: American Association of Immunologists
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
57.57256%
Eosinophils are primarily thought of as terminal effectors of allergic responses and of parasite elimination. However, limited studies suggest a more discrete immunomodulatory role for this leukocyte during these inflammatory responses. In this investigation, we highlight the potential of eosinophils to act as APCs and thus modulators of allergic responses by influencing Th2 cell function. In response to Ag provocation of the allergic lung, eosinophils rapidly trafficked to sites of Ag deposition (airways lumen) and presentation (lung-associated lymph nodes and T cell-rich paracortical zones). Eosinophils from the allergic lung expressed class II MHC peptides, T cell costimulatory molecules (CD80 and CD86), and rapidly internalized and processed Ag that was sampled from within the airway lumen. Ag-loaded eosinophils promoted the production of IL-4, IL-5, and IL-13 in cocultures with in vitro-polarized Th2 cells and induced IL-5 production in a dose-dependent manner from Ag-specific CD4+ T cells isolated from allergic mice. In addition, Ag-loaded eosinophils primed for Th2 cell-driven allergic disease of the lung when transferred to naive mice. Thus, eosinophils have the potential to not only activate Th2 cells to release disease-modulating cytokines but also to assist in priming the immune system for allergic responses. This investigation highlights the potential of eosinophils to not only act as terminal effector cells but also to actively modulate allergic inflammation by amplifying Th2 cell responses.