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1.
Vaccine ; 39(32): 4555-4563, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34154864

RESUMO

Despite the substantial health and economic burden caused by RSV-associated illness, no vaccine is available. The sole licensed treatment (palivizumab), composed of a monoclonal neutralizing antibody, blocks the fusion of the virus to the host cell but does not prevent infection. The development of a safe and efficacious RSV vaccine is therefore a priority, but also a considerable challenge, and new innovative strategies are warranted. Most of the adult population encounter regular RSV infections and can elicit a robust neutralizing antibody response, but unfortunately it wanes over time and reinfections during subsequent seasons are common. One approach to protect the mother and young infant from RSV infection is to administer a vaccine capable of boosting preexisting RSV immunity during pregnancy, which would provide protection to the fetus through passive transfer of maternal antibodies, thus preventing primary RSV infection in newborns during their first months of life. Here, we describe the preclinical evaluation of an epicutaneous RSV vaccine booster that combines epicutaneous patches as a delivery platform and a Synthetic Virus-Like Particles (SVLP)-based vaccine displaying multiple RSV F-protein site II (FsII, palivizumab epitope) mimetic as antigen (V-306). We demonstrated in mice that epicutaneous immunization with V-306 efficiently boosts preexisting immunity induced by the homologous V-306 administered subcutaneously. This boosting was characterized by a significant increase in F- and FsII-specific antibodies capable of competing with palivizumab for its target antigen and neutralize RSV. More importantly, epicutaneous booster immunization with V-306 significantly decreased lung viral replication in experimental mice after intranasal RSV challenge, without inducing enhanced RSV disease. In conclusion, an epicutaneous booster vaccine based on V-306 is safe and efficacious in enhancing RSV preexisting immunity in mice. This needle-free vaccine candidate would be potentially suited as a booster vaccine for vulnerable populations such as young infants via pregnant women, and the elderly.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vacinas contra Vírus Sincicial Respiratório , Vírus Sincicial Respiratório Humano , Idoso , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Feminino , Humanos , Imunização , Recém-Nascido , Camundongos , Gravidez , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Proteínas Virais de Fusão
2.
Inflamm Bowel Dis ; 23(11): 1972-1982, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29019858

RESUMO

BACKGROUND: Although inflammatory bowel disease (IBD) is a failure in maintaining tolerance to the intestinal microbiota, few studies have investigated the use of immunologic tolerance as a treatment approach for IBD. We hypothesized that induction of immune tolerance at a distal site could suppress intestinal inflammation through a process of bystander regulation. METHODS: Epicutaneous tolerance was induced by topical application of ovalbumin (OVA) using a Viaskin patch for 48 hours. In some experiments, a single feed of ovalbumin was used to drive epicutaneous tolerance-induced regulatory T cells (Tregs) to the intestine. The mechanism of tolerance induction was tested using neutralizing antibodies against TGF-ß, IL-10, and Treg depletion using Foxp3-DTR mice. The capacity of skin-draining Tregs, or epicutaneous tolerance, to prevent or treat experimental IBD was tested using T-cell transfer colitis, dextran sodium sulfate (DSS) colitis, and ileitis in SAMP-YITFc mice. Weight loss, colonic inflammatory cytokines and histology were assessed. RESULTS: Epicutaneous exposure to ovalbumin induced systemic immune tolerance by a TGF-ß-dependent, but IL-10 and iFoxp3 Treg-independent mechanism. Skin draining Tregs suppressed the development of colitis. Epicutaneous tolerance to a model antigen prevented intestinal inflammation in the dextran sodium sulfate and SAMP-YITFc models and importantly could halt disease in mice already experiencing weight loss in the T-cell transfer model of colitis. This was accompanied by a significant accumulation of LAP and Foxp3 Tregs in the colon. CONCLUSIONS: This is the first demonstration that epicutaneous tolerance to a model antigen can lead to bystander suppression of inflammation and prevention of disease progression in preclinical models of IBD.


Assuntos
Colite/imunologia , Ileíte/imunologia , Tolerância Imunológica , Linfócitos T Reguladores/imunologia , Animais , Colite/induzido quimicamente , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Ileíte/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-10/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Ovalbumina/administração & dosagem
3.
Cell Mol Immunol ; 14(9): 770-782, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27063469

RESUMO

Allergen-specific immunotherapy has been proposed as an attractive strategy to actively treat food allergy using the following three different immunotherapy routes: oral (OIT), sublingual (SLIT) and epicutaneous (EPIT) immunotherapy. Regulatory T cells (Tregs) have been shown to have a pivotal role in the mechanisms of immunotherapy. The aim of this study was to compare the phenotype and function of Tregs induced in peanut-sensitized BALB/c mice using these three routes of treatment. We show that although EPIT, OIT and SLIT were all able to effectively desensitize peanut-sensitized mice, they induced different subsets of Tregs. Foxp3+ Tregs were induced by the three treatment routes but with greater numbers induced by EPIT. EPIT and OIT also increased the level of LAP+ Tregs, whereas SLIT induced IL-10+ cells. The suppressive activity of EPIT-induced Tregs did not depend on IL-10 but required CTLA-4, whereas OIT acted through both mechanisms and SLIT was strictly dependent on IL-10. Moreover, the three routes influenced the homing properties of induced Tregs differently, with a larger repertoire of chemokine receptors expressed by EPIT-induced Tregs compared with OIT- and SLIT- induced cells, resulting in different protective consequences against allergen exposure. Furthermore, whereas OIT- or SLIT-induced Tregs lost their suppressive activities after treatment was discontinued, the suppressive activities of EPIT-induced Tregs were still effective 8 weeks after the end of treatment, suggesting the induction of a more long-lasting tolerance. In summary, EPIT, OIT and SLIT mediated desensitization through the induction of different subsets of Tregs, leading to important differences in the subsequent protection against allergen exposure and the possible induction of tolerance.


Assuntos
Arachis/efeitos adversos , Imunização , Hipersensibilidade a Nozes e Amendoim/imunologia , Hipersensibilidade a Nozes e Amendoim/urina , Receptores de Retorno de Linfócitos/metabolismo , Imunoterapia Sublingual , Linfócitos T Reguladores/imunologia , Administração Cutânea , Administração Oral , Animais , Feminino , Linfonodos/metabolismo , Camundongos Endogâmicos BALB C , Fenótipo , Baço/metabolismo , Células Th2/imunologia
4.
J Allergy Clin Immunol ; 139(1): 189-201.e4, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27417020

RESUMO

BACKGROUND: The attempt to induce oral tolerance as a treatment for food allergy has been hampered by a lack of sustained clinical protection. Immunotherapy by nonoral routes, such as the skin, may be more effective for the development of maintained tolerance to food allergens. OBJECTIVE: We sought to determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy (EPIT) in a model of food-induced anaphylaxis. METHODS: C3H/HeJ mice were sensitized to ovalbumin (OVA) orally or through the skin and treated with EPIT using OVA-Viaskin patches or oral immunotherapy using OVA. Mice were orally challenged with OVA to induce anaphylaxis. Antigen-specific regulatory T (Treg)-cell induction was assessed by flow cytometry using a transgenic T-cell transfer model. RESULTS: By using an adjuvant-free model of food allergy generated by epicutaneous sensitization and reactions triggered by oral allergen challenge, we found that EPIT induced sustained protection against anaphylaxis. We show that the gastrointestinal tract is deficient in de novo generation of Treg cells in allergic mice. This defect was tissue-specific, and epicutaneous application of antigen generated a population of gastrointestinal-homing LAP+Foxp3- Treg cells. The mechanism of protection was found to be a novel pathway of direct TGF-ß-dependent Treg-cell suppression of mast cell activation, in the absence of modulation of T- or B-cell responses. CONCLUSIONS: Our data highlight the immune communication between skin and gastrointestinal tract, and identifies novel mechanisms by which epicutaneous tolerance can suppress food-induced anaphylaxis.


Assuntos
Anafilaxia/prevenção & controle , Dessensibilização Imunológica/métodos , Hipersensibilidade Alimentar/terapia , Linfócitos T Reguladores/imunologia , Administração Cutânea , Alérgenos/imunologia , Anafilaxia/sangue , Anafilaxia/imunologia , Animais , Arachis/imunologia , Toxina da Cólera/imunologia , Hipersensibilidade Alimentar/sangue , Hipersensibilidade Alimentar/imunologia , Fatores de Transcrição Forkhead/imunologia , Imunoglobulina G/sangue , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Ovalbumina/imunologia , Peptídeos/imunologia , Fator de Crescimento Transformador beta/imunologia
5.
J Control Release ; 243: 146-159, 2016 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-27720994

RESUMO

To put a Respiratory Syncytial Virus (RSV) vaccine onto the market, new vaccination strategies combining scientific and technical innovations need to be explored. Such a vaccine would also need to be adapted to the vaccination of young children that are the principal victims of acute RSV infection. In the present project, we describe the development and the preclinical evaluation of an original epicutaneous RSV vaccine that combines two technologies: Viaskin® epicutaneous patches as a delivery platform and RSV N-nanorings (N) as a subunit antigen. Such a needle-free vaccine may have a better acceptability for the vaccination of sensible population such as infants since it does not require any skin preparation. Moreover, this self-applicative vaccine would overcome some issues associated to injectable vaccines such as the requirement of sterile medical devices, the need of skilled health-care professionals and the necessity of stringent store conditions. Here, we demonstrate that Viaskin® patches loaded with a formulation containing N-nanorings (Viaskin®-N) are highly immunogenic in mice and promotes a Th1/Th17 oriented immune response. More importantly, Viaskin®-N epicutaneous vaccine confers a high level of protection against viral replication upon RSV challenge in mice, without exacerbating clinical symptoms. In swine, which provides the best experimental model for the transcutaneous passage of drug/antigen in human skin, we have shown that GFP fluorescent N-nanorings, delivered epicutaneously with Viaskin® patches, are taken up by epidermal Langerhans cells. We have also demonstrated that Viaskin®-N induced a significant RSV N-specific T-cell response in pig. In conclusion, Viaskin®-N epicutaneous vaccine seems efficient to protect against RSV infection in animal model.


Assuntos
Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Linfócitos T/imunologia , Replicação Viral/imunologia , Administração Cutânea , Animais , Feminino , Células de Langerhans/metabolismo , Camundongos , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vacinas contra Vírus Sincicial Respiratório/farmacocinética , Absorção Cutânea , Especificidade da Espécie , Suínos , Adesivo Transdérmico
7.
Immunotherapy ; 7(12): 1293-305, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26584421

RESUMO

Epicutaneous immunotherapy is a developing technique, aiming at desensitizing patients with food allergy with less risks that oral ingestion or injection could generate. Several clinical trials have been performed and are currently running, in milk and peanut allergy, assessing the safety of the technique and its efficacy. Preclinical models indicate a major role in the mechanisms of desensitization, for example, Tregs and epigenetic modifications.


Assuntos
Dessensibilização Imunológica/métodos , Hipersensibilidade a Leite/terapia , Hipersensibilidade a Amendoim/terapia , Pele/imunologia , Terapias em Estudo/métodos , Administração Cutânea , Adolescente , Animais , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Dessensibilização Imunológica/instrumentação , Modelos Animais de Doenças , Epigênese Genética , Humanos , Lactente , Camundongos , Linfócitos T Reguladores/imunologia , Terapias em Estudo/instrumentação , Adesivo Transdérmico
8.
Vaccine ; 33(30): 3450-5, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26067183

RESUMO

The limited durability of pertussis vaccine-induced protection requires novel approaches to reactivate immunity and limit pertussis resurgence in older children and adults. We propose that periodic boosters could be delivered using a novel epicutaneous delivery system (Viaskin) to deliver optimized pertussis antigens such as genetically-detoxified pertussis toxin (rPT). To best mimic the human situation in which vaccine-induced memory cells persist, whereas antibodies wane, we developed a novel adoptive transfer murine model of pertussis immunity. This allowed demonstrating that a single application of Viaskin delivering rPT and/or pertactin and filamentous hemagglutinin effectively reactivates vaccine-induced pertussis immunity and protects against Bordetella pertussis challenge. Recalling pertussis immunity without needles nor adjuvant may considerably facilitate the acceptance and application of periodic boosters.


Assuntos
Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Bordetella pertussis/imunologia , Imunização Secundária/métodos , Vacina contra Coqueluche/administração & dosagem , Vacina contra Coqueluche/imunologia , Coqueluche/prevenção & controle , Administração Cutânea , Animais , Feminino , Camundongos Endogâmicos BALB C
9.
J Allergy Clin Immunol ; 135(6): 1546-57.e4, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25583102

RESUMO

BACKGROUND: Allergy to cow's milk increases the risk of sensitization to other foods in young children. OBJECTIVES: We sought to evaluate the effect of early epicutaneous immunotherapy (EPIT) on further sensitization to peanut or house dust mite (HDM) in a murine model of sensitization to cow's milk. METHODS: BALB/c mice orally sensitized to milk were epicutaneously treated with a Viaskin patch (DBV Technologies) loaded with milk proteins for 8 weeks. Mice were then sensitized to peanut or HDM. After sensitization to peanut, mice were exposed to a peanut regimen known to induce eosinophilic esophageal inflammation. After sensitization to HDM, mice were challenged with aerosols to HDM, and airway hyperresponsiveness was evaluated by using plethysmography. Humoral response was also analyzed. The role of regulatory T (Treg) cells was evaluated by adoptively transferring Treg cells from milk EPIT-treated mice to naive mice before sensitization to peanut. Protection against anaphylaxis was also investigated. Methylation of the promoter region of transcription factors was analyzed by using PCR assays. RESULTS: In milk-sensitized mice specific EPIT prevented further sensitization to peanut or HDM. EPIT significantly modified the humoral response, reduced TH2 cytokine levels, decreased eosinophilic esophageal infiltration, and suppressed airway hyperresponsiveness. The protective effect was sustained over 2 months. Moreover, the adoptive transfer of milk EPIT Treg cells completely prevented sensitization to peanut and peanut-induced anaphylaxis. Milk EPIT enhanced methylation of the GATA-3 promoter region. CONCLUSIONS: Our results showed that EPIT influences the natural history of allergy and reduces the risk of further sensitization through a Treg cell-dependent mechanism.


Assuntos
Alérgenos/imunologia , Hiper-Reatividade Brônquica/prevenção & controle , Proteção Cruzada , Hipersensibilidade a Leite/terapia , Proteínas do Leite/imunologia , Hipersensibilidade a Amendoim/prevenção & controle , Transferência Adotiva , Alérgenos/administração & dosagem , Alérgenos/isolamento & purificação , Animais , Arachis/química , Arachis/imunologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Criança , Citocinas/genética , Citocinas/imunologia , Metilação de DNA , Dessensibilização Imunológica/métodos , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade a Leite/genética , Hipersensibilidade a Leite/imunologia , Hipersensibilidade a Leite/fisiopatologia , Proteínas do Leite/administração & dosagem , Proteínas do Leite/isolamento & purificação , Hipersensibilidade a Amendoim/genética , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/fisiopatologia , Pletismografia , Regiões Promotoras Genéticas , Pyroglyphidae/química , Pyroglyphidae/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/transplante , Equilíbrio Th1-Th2/efeitos dos fármacos
10.
Clin Transl Allergy ; 2(1): 22, 2012 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-23140259

RESUMO

BACKGROUND: Epicutaneous immunotherapy (EPIT) on intact skin with an epicutaneous delivery system has already been used in preclinical and clinical studies. In epicutaneous vaccination and immunotherapy, the stripping of skin before application of the allergen is suggested to facilitate the passage of allergen through immune cells. OBJECTIVES: The aim of this study was to compare the immunological response induced by EPIT performed on intact and stripped skin in a mouse model of peanut allergy. METHODS: After oral sensitization with peanut and cholera toxin, BALB/c mice were epicutaneously treated using an epicutaneous delivery system (Viaskin® (DBV Technologies, Paris) applied either on intact skin or on stripped skin. Following EPIT, mice received an exclusive oral peanut regimen, aimed at triggering esophageal and jejunal lesions. We assessed eosinophil infiltration by histology, mRNA expression in the esophagus, antibody levels and peripheral T-cell response. RESULTS: EPIT on intact skin significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (2.7 ± 0.9, compared to Sham 19.9 ± 1.5, p < 0.01), mRNA expression of Th2 cytokines in tissue and intestinal villus sub-atrophia (2.9 ± 0.2 vs Sham, 2.1 ± 0.2, p < 0.05). By contrast, EPIT on stripped skin reinforced Th2 systemic immunological response as well as eosinophil infiltration (26.8 ± 15.1), mRNA expression of Th2 cytokines and duodenal villus/crypt-ratio (2.4 ± 0.3). CONCLUSIONS: Epicutaneous allergen-specific immunotherapy needs the integrity of superficial layers of the stratum corneum to warranty safety of treatment and to induce a tolerogenic profile of the immune response.

11.
PLoS One ; 7(2): e31967, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22363776

RESUMO

BACKGROUND: Food allergy may affect the gastrointestinal tract and eosinophilia is often associated with allergic gastrointestinal disorders. Allergy to peanuts is a life-threatening condition and effective and safe treatments still need to be developed. The present study aimed to evaluate the effects of sustained oral exposure to peanuts on the esophageal and jejunal mucosa in sensitized mice. We also evaluated the effects of desensitization with epicutaneous immunotherapy (EPIT) on these processes. METHODS: Mice were sensitized by gavages with whole peanut protein extract (PPE) given with cholera toxin. Sensitized mice were subsequently exposed to peanuts via a specific regimen and were then analysed for eosinophilia in the esophagus and gut. We also assessed mRNA expression in the esophagus, antibody levels, and peripheral T-cell response. The effects of EPIT were tested when intercalated with sensitization and sustained oral peanut exposure. RESULTS: Sustained oral exposure to peanuts in sensitized mice led to severe esophageal eosinophilia and intestinal villus sub-atrophia, i.e. significantly increased influx of eosinophils into the esophageal mucosa (136 eosinophils/mm(2)) and reduced villus/crypt ratios (1.6±0.15). In the sera, specific IgE levels significantly increased as did secretion of Th2 cytokines by peanut-reactivated splenocytes. EPIT of sensitized mice significantly reduced Th2 immunological response (IgE response and splenocyte secretion of Th2 cytokines) as well as esophageal eosinophilia (50 eosinophils/mm(2), p<0.05), mRNA expression of Th2 cytokines in tissue--eotaxin (p<0.05), IL-5 (p<0.05), and IL-13 (p<0.05)--GATA-3 (p<0.05), and intestinal villus sub-atrophia (2.3±0.15). EPIT also increased specific IgG2a (p<0.05) and mRNA expression of Foxp3 (p<0.05) in the esophageal mucosa. CONCLUSIONS: Gastro-intestinal lesions induced by sustained oral exposure in sensitized mice are efficaciously treated by allergen specific EPIT.


Assuntos
Dessensibilização Imunológica/métodos , Doenças do Sistema Digestório/imunologia , Doenças do Sistema Digestório/terapia , Imunização , Hipersensibilidade a Amendoim/imunologia , Hipersensibilidade a Amendoim/terapia , Pele/imunologia , Administração Oral , Animais , Arachis/efeitos adversos , Doenças do Sistema Digestório/sangue , Doenças do Sistema Digestório/induzido quimicamente , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Hipersensibilidade a Amendoim/sangue , Hipersensibilidade a Amendoim/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/imunologia
12.
ISRN Allergy ; 2012: 375735, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23724241

RESUMO

Background. The aim of this study was to compare the efficacy of epicutaneous immunotherapy (EPIT) to sublingual immunotherapy (SLIT) in a model of mice sensitized to Phleum pratense pollen. Methods. BALB/c mice were sensitized by sub-cutaneous route to pollen protein extract mixed treated for 8 weeks, using sham, EPIT, or SLIT. Measurements involved the serological response and cytokine profile from reactivated splenocytes, plethysmography after aerosol challenge to pollen, cell, and cytokine contents in the bronchoalveolar lavages (BALs). Results. After immunotherapy, sIgE was significantly decreased in the treated groups compared to sham (P < 0.001), whereas sIgG2a increased with EPIT and SLIT (P < 0.001 and P < 0.005 versus sham). Reactivated splenocytes secreted higher levels of Th2 cytokines with sham (P < 0.01). Penh values were higher in sham than EPIT and SLIT. Eosinophil recruitment in BAL was significantly reduced only by EPIT (P < 0.01). Conclusion. In this model of mice sensitized to pollen, EPIT was at least as efficient as SLIT.

13.
J Immunol ; 186(10): 5629-37, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21490160

RESUMO

Epicutaneous immunotherapy onto intact skin has proved to be an efficient and safe alternative treatment of allergy in an animal model with various allergens and in children for cow's milk allergy. The aim of this study was to analyze the different steps of the immunological handling of the allergen when deposited on intact skin using an epicutaneous delivery system and its immune consequences in sensitized BALB/c mice. As expected, when applied on intact skin, OVA exhibits neither a passive passage through the skin nor any detectable systemic delivery. The current study demonstrates that, after a prolonged application on intact skin, OVA is taken up by dendritic cells in the superficial layers of the stratum corneum and transported, after internalization, to the draining lymph nodes, with variations according to the previous level of sensitization of the mice. When OVA is applied with the epicutaneous delivery system repeatedly, specific local and systemic responses are down-modulated in association with the induction of regulatory T cells. Besides providing new insights into skin function in the presence of allergens, this study indicates that the skin might have a tolerogenic role, at least when kept intact.


Assuntos
Alérgenos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dessensibilização Imunológica , Pele/imunologia , Administração Cutânea , Alérgenos/metabolismo , Animais , Movimento Celular , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/terapia , Tolerância Imunológica , Imunoterapia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Ovalbumina/imunologia , Linfócitos T Reguladores/imunologia
14.
Int Arch Allergy Immunol ; 154(4): 299-309, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20962535

RESUMO

BACKGROUND: Peanut allergy is a life-threatening condition for which new efficient and safe treatment is expected. We evaluated epicutaneous immunotherapy (EPIT) as a new alternative treatment for peanut allergy in sensitized mice. METHODS: Sixty BALB/c mice were sensitized by gavages with peanut protein extract (PPE) mixed with cholera toxin. An epicutaneous delivery system, coated with 100 µg PPE (Viaskin®, DBV Technologies, Paris, France), was applied to intact skin every week during 48 h (EPIT; n = 20). This group was compared with sensitized mice treated with subcutaneous immunotherapy (SCIT; n = 20), untreated sensitized mice (sham, n = 20), and naive mice (naive; n = 20). After the 8-week treatment, a histamine release test, airway hyperreactivity measurement by plethysmography, and a resistance-compliance measurement after the challenge were performed. Blood and bronchoalveolar lavage were sampled for serology, cytokines, and cytology. RESULTS: Specific IgE (sIgE) increased after sensitization in the EPIT (0.26 µg/ml) and SCIT (0.21 µg/ml) groups and decreased after treatment (0.09 µg/ml, p < 0.001 and 0.06 µg/ml, p < 0.001, respectively). The IgG1/IgG2a ratio decreased in the EPIT and SCIT groups versus the sham group (3.7; p < 0.001 and 2.7; p < 0.01 and 15.1, respectively). At the higher metacholine concentration, enhanced pause values were lower in the EPIT and SCIT groups than in the sham group (7.29, 6.74, and 10.99, p < 0.01, respectively), and did not differ from that of the naive group (5.06). Resistance-compliance was reversed in the treated groups versus the sham group (p < 0.001). IL-4, IL-5, IL-13, eotaxin, and eosinophils were reduced in the BAL of the EPIT and SCIT groups versus the sham group (p < 0.001). CONCLUSION: In peanut-sensitized mice, based on biological and physiological responses, EPIT is as efficient as subcutaneous treatment which is the reference method in immunotherapy.


Assuntos
Dessensibilização Imunológica/métodos , Hipersensibilidade a Amendoim/prevenção & controle , Extratos Vegetais/administração & dosagem , Administração Cutânea , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C
16.
J Pediatr Gastroenterol Nutr ; 42(2): 178-85, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16456412

RESUMO

OBJECTIVES: To determine the doses of polyethylene glycol (PEG) 4000 without additional salts allowing normal bowel habits in childhood functional constipation. METHODS: This multicenter noncomparative study allocated children to 4 groups: 6-12 months, 13 months-3 years, 4-7 years, and 8-15 years. Constipation was defined as <1 stool/d for more than 1 month in children aged 6-12 months and <3 stools/w for more than 3 months in older children. Children randomly received either a nominal or a double starting dose. Treatment scheduled for 3 months could be adapted. Data were collected daily by the parents and rated at each visit by the investigator. RESULTS: In the 96 children included, the median (interquartile) effective daily doses were by groups; 3.75 (2.50-5.00) g, 6.00 (4.00-7.43) g, 11.71 (7.00-16.00) g, and 16.00 (16.00-24.00) g, respectively, i.e., around 0.50 g/day/kg with a potential increment of the maintenance dose with higher initial dosages. More children had a final dosage identical to the initial one when started on the nominal dose (73%) than with the double one (42%, P < 0.003). More than 90% of children recovered normal bowel habits. Fecal soiling ceased in >60% of children with this symptom at enrolment. Fecal mass in the rectum and abdominal pain were markedly reduced and appetite improved. CONCLUSIONS: A daily dose of PEG 4000 around 0.50 g/day/kg in children aged 6 months to 15 years is effective in more than 90% of constipated children and 60% of those with fecal soiling.


Assuntos
Catárticos/uso terapêutico , Constipação Intestinal/tratamento farmacológico , Defecação/efeitos dos fármacos , Polietilenoglicóis/uso terapêutico , Adolescente , Catárticos/efeitos adversos , Criança , Pré-Escolar , Defecação/fisiologia , Relação Dose-Resposta a Droga , Incontinência Fecal/tratamento farmacológico , Incontinência Fecal/epidemiologia , Feminino , Humanos , Lactente , Masculino , Polietilenoglicóis/efeitos adversos , Segurança , Inquéritos e Questionários , Resultado do Tratamento
17.
J Pediatr Gastroenterol Nutr ; 40(4): 406-20, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15795585

RESUMO

Since the introduction of flexible fiberoptic endoscopy in the early 1970s, esophagogastro-duodenoscopy and colonoscopy have become established procedures for the diagnosis, evaluation and treatment of gastrointestinal tract disease in the pediatric population. The development of safe fiberoptic endoscopes specially designed for neonates has allowed visualization of lesions occurring in the first days of life. Despite an increased understanding of neonatal digestive disorders deriving from this new diagnostic modality, there is little consensus on the appropriate use of endoscopic procedures in routine care of neonates. It is the feeling of the authors that widening the indications of endoscopy in the neonatal period might lead to diagnosis of discrete clinical abnormalities, which might improve the care of neonates. The techniques for performing neonatal endoscopies, the appropriate indications, the common normal and pathologic findings and the complications of these procedures are reviewed.


Assuntos
Endoscopia do Sistema Digestório/métodos , Gastroenteropatias/diagnóstico , Sistema Digestório/patologia , Gastroenteropatias/cirurgia , Humanos , Recém-Nascido
18.
Turk J Pediatr ; 45(1): 6-10, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12718363

RESUMO

The purpose of our study was to systematically evaluate gastric acid output in children with long-lasting gastro-esophageal reflux (GER) in order to assess its mechanism and the need for anti-acid treatment. The investigation was carried out in 20 males and 10 females, aged 7.5 +/- 3.8 years, with prolonged (>15 months) clinical manifestations of GER. All underwent routine ambulatory 24-h esophageal pH-monitoring and measurement of gastric acid secretion including gastric basal (BAO) (micromol/kg/h), maximal (MAO) and peak acid outputs (PAO) after pentagastrin (6 microg/kg sec) stimulation. Children with heartburn or abdominal pain underwent upper fiber-endoscopy. In group A (moderate GER, n=12), patients had a normal reflux index (pH<4 below 5.2% of total recording time) despite abnormal Euler and Byrne scoring (median 57, 95% confidence interval 53.5-73.4). In group B (severe GER, n=18, among whom 5 were with grade III esophagitis), reflux index was >5.2%. When considering all children, esophageal pH (%) was significantly correlated with MAO and PAO, r=0.33, p=0.05 and r=0.37, p=0.04, respectively. Children of group B exhibited significantly higher BAO (75, 53.96-137.81), MAO (468, 394.1-671.3) and PAO (617, 518.8-782.3) than those of group A, BAO (27, 10.8-38.5), MAO (266, 243.2-348.2) and PAO (387, 322.5-452.7), p<0.05). The five children of group B with severe esophagitis exhibited significantly higher BAO, MAO and PAO than the other 13 children from the same group and those of group A, p<0.05. Children with long-lasting and severe GER hyper-secrete gastric acid. Individual variations in gastric acid secretion probably account for variations in gastric acid inhibitor requirements. Anti-secretory treatment is justified in children with long-lasting GER and high pH-metric reflux index.


Assuntos
Antiácidos/uso terapêutico , Ácido Gástrico/metabolismo , Refluxo Gastroesofágico/classificação , Adolescente , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Concentração de Íons de Hidrogênio , Masculino , Índice de Gravidade de Doença
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