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1.
Biol Pharm Bull ; 43(1): 36-40, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902929

RESUMO

Allergic rhinitis patients suffer various symptoms such as sneezing, runny nose, and nasal congestion. As disease severity and chronicity progress, nasal hyperresponsiveness (NHR) develops in those patients. During the generation of a mouse allergic rhinitis model, we discovered that immunized mice developed NHR upon repeated nasal antigen challenge. Using genetically modified mice and an originally developed T cell-transferred mouse model, we confirmed the critical role of CD4+ T cells after differentiation into several helper subsets in NHR. On the other hand, immunoglobulin E/mast cell-dependent responses that are critical for evoking nasal symptoms and eosinophils that accumulate in allergic inflammation sites were dispensable. A steroid, but not drugs targeting mast cell-derived mediators, was effective in alleviating NHR. The possible generation of a new means to treat allergic rhinitis by targeting T cell-derived NHR-inducing factors is suggested.


Assuntos
Nariz/imunologia , Rinite Alérgica/imunologia , Linfócitos T/imunologia , Animais , Antígenos/imunologia , Humanos
2.
Genes Cells ; 23(2): 112-116, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29271120

RESUMO

Neuraminidase family enzymes that hydrolyze the terminal sialic acid linkage in biomolecules are involved in various immune responses. We previously showed that Th1 and Th2 cells differentially express several neuraminidases. Herein, the expression of neuraminidases in induced regulatory T (iTreg) cells was investigated in comparison with that in other T-cell subsets. Contrary to the tendency toward higher neuraminidase 1 mRNA expression in in vitro-differentiated Th2 cells, compared to Th1, Th17 and iTreg cells, we observed significantly higher expression of neuraminidase 3 (Neu3) in iTreg cells. Furthermore, the expression of Neu3 in FoxP3+ CD62L- spleen cells was higher than that in FoxP3+ CD62L+ and FoxP3- cells. Lentiviral expression of Neu3 in naïve CD4+ T cells during the stimulation culture led to upregulation of FoxP3 expression. On the basis of these findings, we conclude that Neu3 contributes to the differentiation of iTreg cells by upregulation of FoxP3.


Assuntos
Diferenciação Celular , Neuraminidase/metabolismo , Baço/metabolismo , Linfócitos T Reguladores/citologia , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Células Cultivadas , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neuraminidase/genética , Baço/citologia , Linfócitos T Reguladores/metabolismo
3.
EMBO Rep ; 18(6): 885-893, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28468955

RESUMO

T-cell receptor (TCR)-transgenic mice have been employed for evaluating antigen-response mechanisms, but their non-endogenous TCR might induce immune response differently than the physiologically expressed TCR Nuclear transfer cloning produces animals that retain the donor genotype in all tissues including germline and immune systems. Taking advantage of this feature, we generated cloned mice that carry endogenously rearranged TCR genes from antigen-specific CD4+ T cells. We show that T cells of the cloned mice display distinct developmental pattern and antigen reactivity because of their endogenously pre-rearranged TCRα (rTα) and TCRß (rTß) alleles. These alleles were transmitted to the offspring, allowing us to establish a set of mouse lines that show chronic-type allergic phenotypes, that is, bronchial and nasal inflammation, upon local administrations of the corresponding antigens. Intriguingly, the existence of either rTα or rTß is sufficient to induce in vivo hypersensitivity. These cloned mice expressing intrinsic promoter-regulated antigen-specific TCR are a unique animal model with allergic predisposition for investigating CD4+ T-cell-mediated pathogenesis and cellular commitment in immune diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Hipersensibilidade/imunologia , Técnicas de Transferência Nuclear , Receptores de Antígenos de Linfócitos T/genética , Alelos , Animais , Antígenos/administração & dosagem , Antígenos/imunologia , Clonagem de Organismos , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/imunologia
4.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216735

RESUMO

Bronchial asthma is a chronic disease characterized by reversible airway obstruction, mucus production, and bronchial hyperresponsiveness (BHR). Although Th2 cell-mediated eosinophilic inflammation is an important disease mechanism in the majority of patients with bronchial asthma, recent studies suggest the possible development of Th2-independent airway inflammation and BHR. These non-Th2 endotype patients seem to consist of multiple subgroups, and often do not respond to inhaled corticosteroids. Therefore, to understand the pathogenesis of asthma, it is important to characterize these non-Th2 subgroups. Recently, we demonstrated that Th9 cells induce eosinophil infiltration and eosinophil-independent BHR, and Th9 cells-mediated BHR may be resistant to glucocorticoid. In this review, we summarize the contribution of several T cell subsets in the development of bronchial asthma and introduce our recent study demonstrating Th9 cell-mediated and eosinophil-independent BHR.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Asma/tratamento farmacológico , Asma/imunologia , Asma/metabolismo , Hiper-Reatividade Brônquica/tratamento farmacológico , Humanos , Subpopulações de Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
6.
Int Immunol ; 29(6): 291-300, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28575522

RESUMO

Sublingual immunotherapy (SLIT) is effective against allergic rhinitis, although a substantial proportion of individuals is refractory. Herein, we describe a predictive modality to reliably identify SLIT non-responders (NRs). We conducted a 2-year clinical study in 193 adult patients with Japanese cedar pollinosis, with biweekly administration of 2000 Japanese allergy units of cedar pollen extract as the maintenance dose. After identifying high-responder (HR) patients with improved severity scores and NR patients with unchanged or exacerbated symptoms, differences in 33 HR and 34 NR patients were evaluated in terms of peripheral blood cellular profiles by flow cytometry and serum factors by ELISA and cytokine bead array, both pre- and post-SLIT. Improved clinical responses were seen in 72% of the treated patients. Pre-therapy IL-12p70 and post-therapy IgG1 serum levels were significantly different between HR and NR patients, although these parameters alone failed to distinguish NR from HR patients. However, the analysis of serum parameters in the pre-therapy samples with the Adaptive Boosting (AdaBoost) algorithm distinguished NR patients with high probability within the training data set. Cluster analysis revealed a positive correlation between serum Th1/Th2 cytokines and other cytokines/chemokines in HR patients after SLIT. Thus, processing of pre-therapy serum parameters with AdaBoost and cluster analysis can be reliably used to develop a prediction method for HR/NR patients.


Assuntos
Alérgenos/uso terapêutico , Antígenos de Plantas/uso terapêutico , Biomarcadores/metabolismo , Rinite Alérgica/terapia , Imunoterapia Sublingual/métodos , Adulto , Algoritmos , Alérgenos/imunologia , Antígenos de Plantas/imunologia , Análise por Conglomerados , Cryptomeria/imunologia , Citocinas/metabolismo , Feminino , Humanos , Imunoglobulina G/sangue , Interleucina-12/metabolismo , Masculino , Pessoa de Meia-Idade , Pólen/imunologia , Rinite Alérgica/diagnóstico , Rinite Alérgica/imunologia , Índice de Gravidade de Doença , Equilíbrio Th1-Th2 , Resultado do Tratamento
7.
Allergol Int ; 67S: S25-S31, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29910099

RESUMO

BACKGROUND: We have recently demonstrated that T cell-mediated nasal hyperresponsiveness (NHR) is a representative pathophysiological feature of allergic rhinitis (AR). Although several anti-allergic drugs are used for the treatment of AR, the efficacy of these drugs on T cell-mediated NHR have not been elucidated. In these studies we investigated the effects of dexamethasone (Dex), montelukast (Mk), and chlorpheniramine (Chl) on NHR in antigen-immunized and antigen-specific Th2 cell-transferred mice. METHODS: OVA-immunized BALB/c mice were treated with Dex, Mk, or Chl and challenged intranasally with OVA. We then assessed NHR, the number of inflammatory cells in the nasal lavage fluid (NALF), mRNA expression of Th2 cytokines in the nasal tissue, the population of CD3+CD4+ cells in the nasal lymphoid tissue (NALT), and antigen-specific serum IgE and IgG levels. Antigen-induced NHR and changes in antigen-specific T cells in the NALT were investigated in OVA-specific Th2 cell-transferred mice. RESULTS: Dex significantly suppressed antigen-induced NHR, inflammatory cell infiltration, and IL-4, IL-5, IL-6, and IL-13 expression in immunized mice. Chl was completely ineffective, and only IL-13 expression was suppressed by Mk. None of these drugs affected IgE and IgG production. Antigen-induced NHR and the increase in antigen-specific T cells in the NALT of Th2 cell-transferred mice were inhibited by Dex, but not by Mk or Chl. CONCLUSIONS: Steroids are effective for the reduction of NHR in AR by suppressing the accumulation of inflammatory cells, especially antigen-specific T cells.


Assuntos
Acetatos/farmacologia , Antialérgicos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Clorfeniramina/farmacologia , Dexametasona/farmacologia , Mucosa Nasal/efeitos dos fármacos , Quinolinas/farmacologia , Rinite Alérgica/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Ciclopropanos , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos BALB C , Líquido da Lavagem Nasal/citologia , Líquido da Lavagem Nasal/imunologia , Mucosa Nasal/imunologia , Rinite Alérgica/sangue , Sulfetos
8.
Biol Pharm Bull ; 40(10): 1801-1805, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28966255

RESUMO

CD4+ T cells play a critical role in the development of allergic inflammation in several target organs. Various adhesion molecules are involved in the local recruitment of T cells and other inflammatory cells. We investigated the differential contribution of adhesion molecules to T helper 1 (Th1) and Th2 cell-mediated allergic lung and bowel inflammation by employing their neutralizing antibodies. BALB/c mice transferred with in vitro-differentiated antigen-specific Th1 and Th2 cells were intratracheally or intrarectally challenged with a relevant antigen. Infiltration of infused T cells occurred, along with the accumulation of neutrophils and eosinophils in the lungs of Th1 and Th2 cell-transferred recipients, respectively. Th1-mediated neutrophil and Th2-mediated eosinophil accumulation in the large intestine, which occurred after intrarectal challenge with the antigen, was indicated by the significant elevation of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) activity. Blocking experiments with neutralizing antibodies indicated that intercellular cell adhesion molecule (ICAM)-1; vascular cell adhesion molecule (VCAM)-1; and αL, ß2, and ß7 integrins participate in the accumulation of Th2 cells and eosinophils in the lungs. In contrast, the migration of Th1 cells and neutrophils was diminished by blockage of αL/ß2-integrin and ICAM-1, respectively. Mucosal addressin cell adhesion molecule (MadCAM)-1, vascular cell adhesion molecule (VCAM)-1, α4, ß1, and ß7 contributed to Th1-mediated neutrophilic inflammation in the bowel, though only MadCAM-1, α4, αL, and ß2 were involved in Th2-mediated eosinophilic inflammation. We conclude that distinct sets of adhesion molecules are involved in Th1- and Th2-mediated allergic lung and bowel inflammation.


Assuntos
Moléculas de Adesão Celular/imunologia , Inflamação/imunologia , Intestino Grosso/imunologia , Pulmão/imunologia , Células Th1/imunologia , Células Th2/imunologia , Animais , Anticorpos Monoclonais/farmacologia , Antígenos/imunologia , Eosinófilos/imunologia , Masculino , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Ovalbumina/imunologia
9.
Allergol Int ; 66S: S35-S40, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28755856

RESUMO

BACKGROUND: Reduced responsiveness to corticosteroid therapy is a major problem for patients with severe asthma. Although Th9 cells, along with Th2 cells, facilitate antigen-induced airway eosinophilia and bronchial hyperresponsiveness (BHR), the sensitivity of Th9 cell-mediated responses to steroid therapy remains unknown. In this study, we investigated the effect of dexamethasone (Dex) on antigen-induced airway inflammation in Th9 cell-transferred mice. METHODS: Ovalbumin (OVA)-specific Th2 and Th9 cells were polarized from the CD4+ T cells of DO11.10/RAG-2-/- mice. BALB/c mice were adoptively transferred with Th2 or Th9 cells and challenged with OVA. Dex treatment was performed twice, at 1 h before and at 24 h after the OVA challenge. Following treatment, the number of inflammatory cells in the bronchoalveolar lavage fluid and the bronchial responsiveness to inhaled methacholine were determined. RESULTS: In both the Th2 and Th9 cell-transferred mice, substantial accumulation of eosinophils in the lungs and BHR were induced by challenge with the specific antigen. In the Th2 cell-transferred mice, these responses were significantly diminished by Dex treatment. In contrast, neither cellular infiltration nor BHR was affected by Dex treatment in the Th9 cell-transferred mice, although the Th9 cells substantially expressed glucocorticoid receptor α. Accordingly, antigen-induced interleukin-9 expression in the Th9 cells was attenuated by Dex treatment at least in vitro. Antigen-induced lung infiltration of infused Th2 cells but not Th9 cells was significantly suppressed by Dex. CONCLUSIONS: In contrast to Th2-mediated responses, Th9-mediated airway inflammation was not affected by Dex. Th9 cells might be involved in the developmental mechanisms of steroid-resistant asthma.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Resistência a Medicamentos , Esteroides/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Diferenciação Celular , Citocinas/genética , Citocinas/metabolismo , Dexametasona/farmacologia , Modelos Animais de Doenças , Expressão Gênica , Mediadores da Inflamação , Interleucina-9/genética , Interleucina-9/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
10.
Allergol Int ; 65 Suppl: S24-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27297515

RESUMO

BACKGROUND: Airway accumulation of eosinophils and bronchial hyperresponsiveness (BHR) are prominent features of bronchial asthma, though the contribution of eosinophils to the development of BHR is controversial. Similar to Th2 cell-mediated pathology, Th9 cells, characterized by IL-9-producing activity, have been demonstrated to induce airway eosinophilia and BHR. In this study, we investigated the role of eosinophils in Th9-mediated BHR by employing Th9 cell-transferred murine airway inflammation model. METHODS: Ovalbumin (OVA)-specific Th2 and Th9 cells were differentiated from CD4(+) T cells of DO11.10/RAG-2(-/-) mice in vitro and cytokine-producing activity of those cells was examined. BALB/c mice were adoptively transferred with Th2 or Th9 cells and challenged with OVA. Then, the number of inflammatory cells in bronchoalveolar lavage fluid and bronchial responsiveness to inhaled methacholine were determined. RESULTS: Both in Th2 and Th9 cell-transferred mice, substantial accumulation of eosinophils in the lungs and BHR were induced by challenge with specific antigen. Nevertheless, an essential and dispensable role of eosinophils in Th2- and Th9-mediated BHR, respectively, was demonstrated by employing eosinophil-deficient mice. The neutralization of IL-9 as well as deficiency of IL-10 in the donor cells did not affect Th9-mediated BHR. CONCLUSIONS: In contrast to Th2-mediated and eosinophil-dependent BHR, Th9 could induce BHR independently from eosinophils and its characteristic cytokines, IL-9 and IL-10.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/metabolismo , Eosinófilos/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígenos/imunologia , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Diferenciação Celular/imunologia , Citocinas/biossíntese , Modelos Animais de Doenças , Eosinófilos/metabolismo , Contagem de Leucócitos , Camundongos , Camundongos Knockout , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo
13.
Allergol Int ; 63 Suppl 1: 29-35, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24809373

RESUMO

BACKGROUND: The eosinophil is deeply associated with the pathogenesis of bronchial asthma and other allergic diseases. We recently identified a novel eosinophil-specific cell surface molecule, major facilitator super family domain containing 10 (Mfsd10). A monoclonal antibody (mAb) against Mfsd10 (M2) showed selective binding and neutralizing activities for eosinophils. However, the relative potency of the blockage of Mfsd10 and other eosinophil-specific molecules for the treatment of allergic diseases has not been evaluated. Therefore, in this study, the effects of M2 and an anti-Siglec-F mAb on antigen-immunized and antigen-specific Th2 cell-transferred murine eosinophilic inflammation models were comparatively investigated. METHODS: Ovalbumin (OVA)-specific Th2 cells were differentiated from naïve CD4+ T cells of DO11.10/RAG-2-/- mice in vitro and cytokine producing activity of the Th2 cells was examined. OVA-immunized and Th2 cell-transferred BALB/c mice were treated with M2 or anti-Siglec-F and challenged with OVA. Then the number of inflammatory cells and the concentration of IL-5 in the bronchoalveolar lavage fluid (BALF) were determined. RESULTS: Antigen-specific Th2 cells produced large amounts of IL-4, IL-5 and IL-13 but not IL-17A or IFN-γ. Administration of M2 significantly suppressed antigen-induced lung eosinophil infiltration both in OVA-immunized and Th2 cell-transferred mice. The potency as well as selectivity of M2 for down-regulating eosinophils was quite similar to that of anti-Siglec-F. Both mAbs did not affect antigen-induced IL-5 production in the lungs. CONCLUSIONS: Mfsd10 as well as Siglec-F could be an effective target to treat eosinophil-related disorders including bronchial asthma.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunossupressores/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Eosinofilia Pulmonar/imunologia , Células Th2/imunologia , Animais , Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Feminino , Interleucina-5/biossíntese , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Knockout , Eosinofilia Pulmonar/tratamento farmacológico , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/patologia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico , Células Th2/metabolismo
15.
Plant Biotechnol J ; 11(1): 66-76, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23066780

RESUMO

Transgenic rice accumulating the modified major Japanese cedar pollen allergens, Cryptomeria japonica 1 (Cry j 1) and Cryptomeria japonica 2 (Cry j 2), which were deconstructed by fragmentation and shuffling, respectively, in the edible part of the seed was generated by transformation of a good-tasting rice variety, 'Koshihikari'. These modified cedar pollen antigens were deposited in ER-derived protein bodies (PB-I), which are suitable for delivery to the mucosal immune system in gut-associated lymphoid tissue when orally administered because antigens bioencapsulated in PB-I are resistant against hydrolysis by intestinal enzymes and harsh environments. Mice fed transgenic seeds daily for three weeks and then challenged with crude cedar pollen allergen showed marked suppression of allergen-specific CD4(+) T-cell proliferation, IgE and IgG levels compared with mice fed nontransgenic rice seeds. As clinical symptoms of pollinosis, sneezing frequency and infiltration of inflammatory cells such as eosinophils and neutrophils were also significantly reduced in the nasal tissue. These results imply that oral administration of transgenic rice seeds containing the structurally disrupted Cry j 1 and Cry j 2 antigens, serving as universal antigens, is a promising approach for specific immunoprophylaxis against Japanese cedar pollinosis.


Assuntos
Antígenos de Plantas/administração & dosagem , Cryptomeria/efeitos adversos , Imunoterapia/métodos , Oryza/genética , Proteínas de Plantas/administração & dosagem , Pólen/efeitos adversos , Rinite Alérgica Sazonal/tratamento farmacológico , Administração Oral , Animais , Antígenos de Plantas/imunologia , Cryptomeria/química , Camundongos , Agricultura Molecular/métodos , Proteínas de Plantas/imunologia , Planticorpos/administração & dosagem , Plantas Geneticamente Modificadas , Pólen/química , Pólen/imunologia , Rinite Alérgica Sazonal/imunologia , Sementes/química
16.
Int Arch Allergy Immunol ; 161 Suppl 2: 164-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23711869

RESUMO

Allergen-specific immunotherapy (IT) has been shown to provide clinical benefit for patients with allergic diseases. At present, subcutaneous and sublingual ITs are mainly authorized for clinical treatment. Oral administration of allergens seems to be the easiest way to achieve IT, though it has yet to be translated to the clinical setting, mainly due to the requirement of a large amount of allergens. Plants, especially rice seeds, have recently been recognized as superior allergen carriers for oral administration, because of their high productivity, stability and safety. Therefore, in order to establish clinically applicable oral IT, we have been developing transgenic rice seeds (Tg rice), in which major epitopes of cedar pollen allergens or house-dust mites (HDM) are expressed. The efficacy of this orally administered Tg rice was confirmed in murine models of allergic rhinitis and bronchial asthma. In the safety study of the Tg rice, no adverse effects on cynomolgus macaques were observed. In this review, we summarized the current state and future prospects of allergen-specific IT, focusing particularly on oral IT with allergen-expressing Tg rice.


Assuntos
Alérgenos/imunologia , Dessensibilização Imunológica , Hipersensibilidade/terapia , Oryza , Sementes , Administração Oral , Alérgenos/administração & dosagem , Animais , Dessensibilização Imunológica/efeitos adversos , Modelos Animais de Doenças , Humanos , Camundongos , Plantas Geneticamente Modificadas
17.
Int Arch Allergy Immunol ; 161 Suppl 2: 125-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23711863

RESUMO

BACKGROUND: Immunoglobulin E (IgE) is important for the development of allergic rhinitis (AR), though the contribution of IgE to the infiltration of eosinophils in the nasal mucosa has not been fully elucidated. In this study, antigen-induced sneezing and nasal eosinophil accumulation were comparatively investigated in anti-ovalbumin (OVA)-IgE transgenic (Tg) and wild-type (WT) mice. METHODS: Tg and OVA-immunized WT mice were intranasally challenged with OVA. Antigen-specific serum IgE level, sneezing and infiltration of eosinophil into the nasal cavity were then examined. RESULTS: The level of serum OVA-specific IgE in Tg mice was significantly higher than that in antigen-immunized WT mice. Compared to saline challenge, intranasal challenge with OVA significantly induced sneezing in both Tg and immunized WT mice. However, antigen-induced nasal eosinophil infiltration was observed in immunized WT mice but not in Tg mice. CONCLUSIONS: IgE-mediated responses might not play a crucial role in antigen-induced eosinophil infiltration in AR.


Assuntos
Antígenos/imunologia , Eosinófilos/imunologia , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Mucosa Nasal/imunologia , Animais , Feminino , Hipersensibilidade/patologia , Camundongos , Camundongos Transgênicos , Mucosa Nasal/patologia , Ovalbumina/imunologia , Rinite Alérgica Perene/imunologia , Rinite Alérgica Perene/patologia
19.
Int Arch Allergy Immunol ; 158 Suppl 1: 66-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22627369

RESUMO

BACKGROUND: Oral immunotherapy is potentially useful for the treatment of allergic diseases. We previously demonstrated that allergen-induced airway inflammation and immunoglobulin E (IgE) production in mice were suppressed by oral administration of high-dose transgenic (Tg) rice seeds (approximately 50 g/kg/day) expressing a T cell epitope of Dermatophagoides pteronyssinus group 1 allergen (Der p 1). However, this amount of Tg rice seeds was not realistic in our daily life. In this study, allergen-induced airway inflammation and IgE production following oral immunotherapy with a realistic (lowest) dose of Tg rice seeds were investigated. METHODS: Mice orally administered with Tg or non-Tg rice seeds at approximately 5 g/kg/day for 1 week were immunized with recombinant Der p 1, and then challenged with the corresponding allergen. The infiltration of inflammatory cells into the airways and the levels of allergen-specific serum IgE were examined. RESULTS: Low-dose oral administration of Tg rice seeds significantly inhibited the allergen-induced infiltration of eosinophils and lymphocytes into the airways, but allergen-specific IgE synthesis was not changed. CONCLUSIONS: Low-dose oral immunotherapy with Tg rice seeds could suppress allergen-induced airway inflammation through mechanisms other than the downregulation of IgE synthesis.


Assuntos
Dessensibilização Imunológica , Oryza/imunologia , Plantas Geneticamente Modificadas/imunologia , Pneumonia/terapia , Sementes/imunologia , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Proteínas de Artrópodes/imunologia , Cisteína Endopeptidases/imunologia , Feminino , Imunoglobulina E/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/imunologia
20.
Mol Genet Metab ; 102(1): 91-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20855224

RESUMO

P-glycoprotein (P-gp), the product of the MDR1 gene, shows large interindividual variations in expression, which leads to differences in the pharmacokinetics of the substrate drugs. The functions of single nucleotide polymorphisms located in the nuclear receptor-responsive element of the 5'-flanking region in the human MDR1 gene were analyzed in order to clarify the mechanism underlying the interindividual variation in P-gp expression. Electrophoretic mobility shift assays revealed that the -7833C>T substitution in the nuclear receptor-responsive region of MDR1 decreases the binding affinities of four nuclear receptors to their responsive elements: vitamin D receptor (VDR), thyroid hormone receptor (TR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). A reporter gene assay revealed that the C-to-T substitution at -7833 also reduces the transcriptional activation of MDR1 by VDR, TRß, CAR, and PXR. However, another SNP (-1211T>C substitution), which results in the formation of a xenobiotic responsive element-like sequence and a hypoxia responsive element-like sequence, failed to affect the aryl hydrocarbon receptor-dependent and hypoxia-induced transcriptional activation of MDR1. Although the frequency of the -7833C>T substitution in MDR1 is relatively low, the SNP is crucial because it may alter the pharmacokinetics of P-gp substrates in a small subset of the population.


Assuntos
Região 5'-Flanqueadora/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP , Sequência de Bases , Receptor Constitutivo de Androstano , Ensaio de Desvio de Mobilidade Eletroforética , Genes Reporter , Humanos , Dados de Sequência Molecular , Polinucleotídeos/metabolismo , Receptor de Pregnano X , Ligação Proteica , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Transcrição Gênica , Células Tumorais Cultivadas
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