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1.
J Allergy Clin Immunol ; 123(1): 138-145.e5, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19056111

RESUMO

BACKGROUND: Respiratory syncytial virus (RSV)-specific IgE is a component of the host response to RSV infection, but its role in the subsequent enhancement of altered airway responsiveness is unknown. OBJECTIVE: To define the role of RSV-specific IgE in the enhancement of airway responsiveness on reinfection of newborn mice. METHODS: Mice were infected as newborns with RSV and were reinfected 5 weeks later. The role of IgE was determined by documenting RSV-specific IgE response after neonatal infection, and by assessing airway responsiveness on reinfection. RESULTS: After neonatal infection, wild-type (WT) mice developed an RSV-specific IgE response. On reinfection, these mice developed enhanced airway hyperresponsiveness (AHR), airway eosinophilia, and mucus hyperproduction, and their T-cell cytokine response was skewed toward a T(H)2 phenotype. None of these altered responses developed on reinfection of IL-4(-/-)/IL-13(-/-) mice, and no RSV-specific IgE could be detected after neonatal infection of these mice. Fc epsilon RI(-/-) mice did not develop the enhanced AHR on reinfection, and airway eosinophilia and mucus production were significantly attenuated. These responses could be restored in deficient mice reconstituted with WT mast cells. In RSV-infected newborn WT mice, administration of anti-IgE prevented the enhancement of AHR and attenuated eosinophilia and mucus hyperproduction on reinfection, an effect that was associated with diminished T(H)2 cytokine production and increased IFN-gamma production. CONCLUSION: Respiratory syncytial virus-specific IgE enhances the development of T(H)2-biased airway responsiveness on reinfection of mice initially infected as newborns.


Assuntos
Anticorpos Antivirais/imunologia , Imunoglobulina E/imunologia , Hipersensibilidade Respiratória/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Células Th2/imunologia , Animais , Animais Recém-Nascidos , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de IgE/genética , Receptores de IgE/imunologia , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/genética
2.
J Allergy Clin Immunol ; 121(1): 88-94, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17936889

RESUMO

BACKGROUND: RNA interference is an endogenous cellular mechanism in which short interfering RNAs (siRNAs) direct the sequence specific degradation of a target mRNA. siRNAs can be synthesized with chemical modifications to increase stability and reduce double-stranded RNA-induced immune responses without affecting their ability to elicit degradation of target mRNA. OBJECTIVES: This study examined the use of chemically modified siRNAs in a mouse model of allergen-induced airway hyperresponsiveness. METHODS: Chemically modified siRNAs were designed and screened in a cell-based reporter assay. The most potent siRNAs were then screened in bone marrow-derived mast cells to demonstrate efficacy in primary cells. RESULTS: A candidate siRNA was formulated and administered to sensitized mice just before airway challenge with allergen. Administration of the siRNA was shown to reduce airway resistance significantly in sensitized and challenged mice by 60%, whereas a control siRNA had no effect. CONCLUSION: These data demonstrate the effectiveness of introducing targeted siRNAs to prevent induction of allergen-induced airway dysfunction and suggest potential therapeutic applications.


Assuntos
Hiper-Reatividade Brônquica/terapia , Interleucina-13/metabolismo , Interferência de RNA , RNA Interferente Pequeno/uso terapêutico , Animais , Células da Medula Óssea , Hiper-Reatividade Brônquica/etiologia , Modelos Animais de Doenças , Feminino , Genes Reporter , Humanos , Interleucina-13/genética , Mastócitos , Camundongos , Camundongos Endogâmicos BALB C , RNA Interferente Pequeno/síntese química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Organismos Livres de Patógenos Específicos , Resultado do Tratamento
3.
Am J Respir Cell Mol Biol ; 38(5): 501-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18063836

RESUMO

The female hormone estrogen is an important factor in the regulation of airway function and inflammation, and sex differences in the prevalence of asthma are well described. Using an animal model, we determined how sex differences may underlie the development of altered airway function in response to allergen exposure. We compared sex differences in the development of airway hyperresponsiveness (AHR) after allergen exposure exclusively via the airways. Ovalbumin (OVA) was administered by nebulization on 10 consecutive days in BALB/c mice. After methacholine challenge, significant AHR developed in male mice but not in female mice. Ovariectomized female mice showed significant AHR after 10-day OVA inhalation. ICI182,780, an estrogen antagonist, similarly enhanced airway responsiveness even when administered 1 hour before assay. In contrast, 17beta-estradiol dose-dependently suppressed AHR in male mice. In all cases, airway responsiveness was inhibited by the administration of a neurokinin 1 receptor antagonist. These results demonstrate that sex differences in 10-day OVA-induced AHR are due to endogenous estrogen, which negatively regulates airway responsiveness in female mice. Cumulatively, the results suggest that endogenous estrogen may regulate the neurokinin 1-dependent prejunctional activation of airway smooth muscle in allergen-exposed mice.


Assuntos
Alérgenos/administração & dosagem , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Estrogênios/fisiologia , Ovalbumina/administração & dosagem , Caracteres Sexuais , Alérgenos/imunologia , Animais , Hiper-Reatividade Brônquica/metabolismo , Modelos Animais de Doenças , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Moduladores de Receptor Estrogênico/administração & dosagem , Feminino , Fulvestranto , Masculino , Cloreto de Metacolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Neurocinina A/antagonistas & inibidores , Neurocinina A/fisiologia , Antagonistas dos Receptores de Neurocinina-1 , Ovalbumina/imunologia
4.
Am J Respir Crit Care Med ; 177(2): 208-18, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17962634

RESUMO

RATIONALE: Severe respiratory syncytial virus (RSV) bronchiolitis has been associated with deficient IFN-gamma production in humans, but the role of this cytokine in determining the outcome of reinfection is unknown. OBJECTIVES: To define the role of IFN-gamma in the development of RSV-mediated airway hyperresponsiveness (AHR) and lung histopathology in mice. METHODS: Wild-type (WT) and IFN-gamma knockout mice were infected with RSV in the newborn or weaning stages and reinfected 5 weeks later. Airway responses were assessed on Day 6 after the primary or secondary infection. MEASUREMENTS AND MAIN RESULTS: Both WT and IFN-gamma knockout mice developed similar levels of AHR and airway inflammation after primary infection. After reinfection, IFN-gamma knockout mice, but not WT mice, developed AHR, airway eosinophilia, and mucus hyperproduction. Intranasal administration of IFN-gamma during primary infection but not during reinfection prevented the development of these altered airway responses on reinfection in IFN-gamma knockout mice. Adoptive transfer of WT T cells into IFN-gamma knockout mice before primary infection restored IFN-gamma production in the lungs and prevented the development of altered airway responses on reinfection. Treatment of mice with IFN-gamma during primary neonatal infection prevented the enhancement of AHR and the development of airway eosinophilia and mucus hyperproduction on reinfection. CONCLUSIONS: IFN-gamma production during primary RSV infection is critical to the development of protection against AHR and lung histopathology on reinfection. Provision of IFN-gamma during primary infection in infancy may be a potential therapeutic approach to alter the course of RSV-mediated long-term sequelae.


Assuntos
Interferon gama/biossíntese , Pulmão/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sinciciais Respiratórios , Animais , Animais Recém-Nascidos , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/prevenção & controle , Interferon gama/deficiência , Interferon gama/genética , Interferon gama/uso terapêutico , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Knockout , Recidiva , Infecções por Vírus Respiratório Sincicial/etiologia , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Linfócitos T/imunologia , Carga Viral
5.
J Immunol ; 179(5): 2787-96, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17709492

RESUMO

CD4+ T cells, particularly Th2 cells, play a pivotal role in allergic airway inflammation. However, the requirements for interactions between CD4+ and CD8+ T cells in airway allergic inflammation have not been delineated. Sensitized and challenged OT-1 mice in which CD8+ T cells expressing the transgene for the OVA(257-264) peptide (SIINFEKL) failed to develop airway hyperresponsiveness (AHR), airway eosinophilia, Th2 cytokine elevation, or goblet cell metaplasia. OT-1 mice that received naive CD4+IL-4+ T cells but not CD4+IL-4- T cells before sensitization developed all of these responses to the same degree as wild-type mice. Moreover, recipients of CD4+IL-4+ T cells developed significant increases in the number of CD8+IL-13+ T cells in the lung, whereas sensitized OT-1 mice that received primed CD4+ T cells just before challenge failed to develop these responses. Sensitized CD8-deficient mice that received CD8+ T cells from OT-1 mice that received naive CD4+ T cells before sensitization increased AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged with allergen. In contrast, sensitized CD8-deficient mice receiving CD8+ T cells from OT-1 mice without CD4+ T cells developed reduced AHR and eosinophil numbers in bronchoalveolar lavage fluid when challenged. These data suggest that interactions between CD4+ and CD8+ T cells, in part through IL-4 during the sensitization phase, are essential to the development of CD8+IL-13+ T cell-dependent AHR and airway allergic inflammation.


Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interleucina-4/metabolismo , Transferência Adotiva , Animais , Asma/prevenção & controle , Hiper-Reatividade Brônquica/prevenção & controle , Antígenos CD4/análise , Proteínas do Ovo/genética , Proteínas do Ovo/metabolismo , Inflamação/imunologia , Inflamação/prevenção & controle , Interleucina-4/administração & dosagem , Interleucina-4/genética , Camundongos , Camundongos Transgênicos , Ovalbumina/genética , Ovalbumina/metabolismo , Fragmentos de Peptídeos , Transgenes
6.
J Allergy Clin Immunol ; 119(5): 1241-50, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17353041

RESUMO

BACKGROUND: IL-10 affects dendritic cell (DC) function, but the effects on airway hyperresponsiveness (AHR) and inflammation are not defined. OBJECTIVE: We sought to determine the importance of IL-10 in regulating DC function in allergen-induced AHR and airway inflammation. METHODS: DCs were generated from bone marrow in the presence or absence of IL-10. In vivo IL-10-treated DCs from IL-10(+/+) and IL-10(-/-) donors pulsed with ovalbumin (OVA) were transferred to naive or sensitized mice before challenge. In recipient mice AHR, cytokine levels, cell composition of bronchoalveolar lavage (BAL) fluid, and lung histology were monitored. RESULTS: In vitro, IL-10-treated DCs expressed lower levels of CD11c, CD80, and CD86; expressed lower levels of IL-12; and suppressed T(H)2 cytokine production. In vivo, after transfer of OVA-pulsed IL-10-treated DCs, naive mice did not have AHR, airway eosinophilia, T(H)2 cytokine increase in BAL fluid, or goblet cell metaplasia when challenged, and in sensitized and challenged mice IL-10-treated DCs suppressed these responses. Levels of IL-10 in BAL fluid and numbers of lung CD4(+)IL-10(+) T cells were increased in mice that received OVA-pulsed IL-10-treated DCs. Transfer of IL-10-treated DCs from IL-10-deficient mice were ineffective in suppressing the responses in sensitized and challenged mice. CONCLUSIONS: These data demonstrate that IL-10-treated DCs are potent suppressors of the development of AHR, inflammation, and T(H)2 cytokine production; these regulatory functions are at least in part through the induction of endogenous (DC) production of IL-10. CLINICAL IMPLICATIONS: Modification of DC function by IL-10 can attenuate lung allergic responses, including the development of AHR.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Células Dendríticas/imunologia , Inflamação/imunologia , Interleucina-10/metabolismo , Transferência Adotiva , Animais , Citocinas/biossíntese , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Ovalbumina/imunologia
7.
Am J Respir Cell Mol Biol ; 35(2): 147-54, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16528011

RESUMO

RANTES (CC chemokine ligand 5) contributes to airway inflammation through accumulation of eosinophils, but the exact role of RANTES (CCL5) is not defined. C57BL/6 mice, sensitized by injection of ovalbumin (OVA) on Days 1 and 14, were challenged with OVA on Days 28, 29, and 30 (3 challenges, short-term-challenge model) or on Days 28, 29, 30, 36, 40, 44, and 48 (7 challenges, repeated-challenge model) and evaluated 48 h later. Anti-mouse RANTES was given intravenously, and recombinant mouse RANTES or PBS was given intratracheally. These reagents were given on Days 28, 29, and 30 in the short-term-challenge study and on Days 44 and 48 in the repeated-challenge study. After short-term challenge, there were no effects after administration of anti-RANTES or RANTES. In the repeated-challenge study, although control mice showed a decrease in airway hyperresponsiveness, administration of anti-RANTES sustained and enhanced airway hyperresponsiveness and increased goblet cell numbers. In contrast, administration of RANTES normalized airway function but reduced goblet cell numbers. IL-12 and IFN-gamma levels in BAL decreased in the anti-RANTES group and increased in the RANTES group. IFN-gamma-producing CD4 T cells in lung, and IFN-gamma production from lung T cells in response to OVA in the anti-RANTES group, were significantly decreased but were increased in the RANTES group. Anti-IFN-gamma, administered with RANTES, decreased the effects of RANTES on AHR after repeated challenge. These data indicate that RANTES plays a role in the regulation of airway function after repeated allergen challenge, in part through modulation of levels of IFN-gamma and IL-12.


Assuntos
Alérgenos/imunologia , Quimiocina CCL5/fisiologia , Ovalbumina/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Quimiocina CCL5/administração & dosagem , Quimiocina CCL5/antagonistas & inibidores , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Feminino , Interferon gama/análise , Interferon gama/biossíntese , Interleucina-12/análise , Interleucina-12/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo
8.
J Immunol ; 175(3): 1876-83, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16034131

RESUMO

Respiratory syncytial virus (RSV) infection in early life is suspected to play a role in the development of post-bronchiolitis wheezing and asthma. Reinfection is common at all ages, but factors that determine the development of altered airway function after reinfection are not well understood. This study was conducted in a mouse model to define the role of age in determining the consequences on airway function after reinfection. Mice were infected shortly after birth or at weaning and were reinfected 5 wk later, followed by assessment of airway function, airway inflammation, and lung histopathology. Infection of mice at weaning elicited a protective airway response upon reinfection. In this age group, reinfection resulted in increased airway inflammation, but without development of airway hyperresponsiveness (AHR) or eosinophilia and decreased IL-13 levels. By contrast, neonatal infection failed to protect the airways and resulted in enhanced AHR after reinfection. This secondary response was associated with the development of airway eosinophilia, increased IL-13 levels, and mucus hyperproduction. Both CD4- and CD8-positive T cells were a source of IL-13 in the lung, and inhibition of IL-13 abolished AHR and mucus production in these mice. Inoculation of UV-inactivated virus failed to elicit these divergent responses to reinfection, emphasizing the requirement for active lung infection during initial exposure. Thus, neonatal RSV infection predisposes to the development of airway eosinophilia and enhanced AHR via an IL-13-dependent mechanism during reinfection, whereas infection at a later age protects against the development of these altered airway responses after reinfection.


Assuntos
Envelhecimento/imunologia , Animais Recém-Nascidos/imunologia , Animais Recém-Nascidos/virologia , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/fisiopatologia , Interleucina-13/biossíntese , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Animais , Hiper-Reatividade Brônquica/prevenção & controle , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/fisiopatologia , Eosinofilia/imunologia , Eosinofilia/fisiopatologia , Eosinofilia/virologia , Interleucina-13/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Desmame
9.
Am J Physiol Lung Cell Mol Physiol ; 288(4): L761-70, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15608150

RESUMO

The mechanisms by which respiratory syncytial virus (RSV) infection causes airway hyperresponsiveness (AHR) are not fully established. We hypothesized that RSV infection may alter the expression of airway sensory neuropeptides, thereby contributing to the development of altered airway function. BALB/c mice were infected with RSV followed by assessment of airway function, inflammation, and sensory neuropeptide expression. After RSV infection, mice developed significant airway inflammation associated with increased airway resistance to inhaled methacholine and increased tracheal smooth muscle responsiveness to electrical field stimulation. In these animals, substance P expression was markedly increased, whereas calcitonin gene-related peptide (CGRP) expression was decreased in airway tissue. Prophylactic treatment with Sendide, a highly selective antagonist of the neurokinin-1 receptor, or CGRP, but not the CGRP antagonist CGRP(8-37), inhibited the development of airway inflammation and AHR in RSV-infected animals. Therapeutic treatment with CGRP, but not CGRP(8-37) or Sendide, abolished AHR in RSV-infected animals despite increased substance P levels and previously established airway inflammation. These data suggest that RSV-induced airway dysfunction is, at least in part, due to an imbalance in sensory neuropeptide expression in the airways. Restoration of this balance may be beneficial for the treatment of RSV-mediated airway dysfunction.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Pulmão/metabolismo , Ácido Pirrolidonocarboxílico/análogos & derivados , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sincicial Respiratório Humano/patogenicidade , Animais , Antieméticos/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Peptídeo Relacionado com Gene de Calcitonina/genética , Humanos , Inflamação/etiologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Antagonistas dos Receptores de Neurocinina-1 , Fragmentos de Peptídeos/farmacologia , Ácido Pirrolidonocarboxílico/farmacologia , Substância P/farmacologia
10.
J Allergy Clin Immunol ; 114(4): 820-5, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15480321

RESUMO

BACKGROUND: Eosinophils play a major role in allergic airway inflammation because of their ability to release toxic mediators. In addition, they are able to migrate toward draining thoracic lymph nodes (TLNs) after intratracheal administration, where they can function as antigen-presenting cells. OBJECTIVE: In this study, we evaluated in vivo eosinophil migration toward the TLN after allergen sensitization and analyzed expression of molecules involved in antigen presentation. METHODS: Mice were sensitized by intraperitoneal injection of ovalbumin on days 1 and 10 and challenged once intranasally with ovalbumin on day 20. The kinetics of eosinophilia was evaluated in blood, lung tissue homogenate, bronchoalveolar lavage fluid, and TLN. Cell surface staining was analyzed by flow cytometry. RESULTS: The kinetics of eosinophil recruitment was similar in TLN, lung tissue, and blood, beginning at 12 hours and peaking at 48 hours after allergen challenge. Approximately 70% of TLN eosinophils expressed MHC class II molecules, compared with less than 25% in blood and lungs. Moreover, TLN eosinophils expressed higher levels of MHC class II and CD86 compared with blood and lung eosinophils. Most eosinophils expressed CD80 and CD54, whereas only a few eosinophils expressed CD40. Eosinophils in lungs and TLN appeared to be activated with lower CD62-ligand expression compared with blood eosinophils. CONCLUSION: The presence of eosinophils with a different phenotype in the TLN at early time points after allergen challenge of sensitized mice supports their capacity to serve as antigen-presenting cells, sustaining allergic/inflammatory responses in the airways.


Assuntos
Alérgenos/imunologia , Quimiotaxia de Leucócito/imunologia , Eosinófilos/imunologia , Linfonodos/imunologia , Administração por Inalação , Alérgenos/administração & dosagem , Animais , Apresentação de Antígeno/imunologia , Antígenos CD/imunologia , Testes de Provocação Brônquica , Feminino , Genes MHC da Classe II/imunologia , Camundongos , Tórax
11.
Am J Respir Crit Care Med ; 170(9): 952-9, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15306536

RESUMO

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.


Assuntos
Anticorpos Antivirais/análise , Asma/fisiopatologia , Hiper-Reatividade Brônquica/imunologia , Imunoglobulina E/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Asma/imunologia , Sequência de Bases , Hiper-Reatividade Brônquica/virologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Probabilidade , RNA Mensageiro/análise , Infecções por Vírus Respiratório Sincicial/fisiopatologia , Vírus Sinciciais Respiratórios/imunologia , Sensibilidade e Especificidade
12.
J Immunol ; 173(2): 1298-306, 2004 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15240723

RESUMO

Age is an important factor in determining the quantity and quality of immune responses when challenged with allergen. In a model of allergen-induced airway hyperresponsiveness and inflammation, where the sensitization phase and challenge phases can be dissociated in time, we examined the impact of age on these two phases. Sensitization of young mice (1-20 wk), but not older animals (30-40 wk), led to the development of airway hyperresponsiveness, airway eosinophilia, Th2 cytokine responses, and allergen-specific IgE, regardless of the age when the challenge phase was conducted. Thus, age at the time of initial sensitization was shown to be the critical factor dictating the nature of the response to later allergen challenge, as older mice remained responsive to allergen challenge if sensitized at a young age. These effects were shown to be mediated by lung T cells from sensitized young mice. Moreover, the failure of old sensitized mice to mediate these effects was shown not to be the result of active suppression of the responses. These data define the importance of age at initial allergen exposure in dictating subsequent responses in the lung when exposed to allergen and may help to define why asthma, even in adults, is most often initiated in early childhood.


Assuntos
Alérgenos/imunologia , Hipersensibilidade/imunologia , Sistema Respiratório/imunologia , Fatores Etários , Animais , Citocinas/metabolismo , Camundongos , Sistema Respiratório/metabolismo
13.
Am J Respir Cell Mol Biol ; 30(6): 830-6, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14754758

RESUMO

The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O(3) exposure in mice was investigated. Exposure of C57/BL6 mice to O(3) at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O(3) exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O(3) exposure. Administration of (human) IL-1Ra before and after O(3) exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O(3) exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O(3) exposure. In summary, acute exposure to O(3) induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.


Assuntos
Hiper-Reatividade Brônquica/imunologia , Ozônio/imunologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/imunologia , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Broncoconstritores/farmacologia , Citocinas/metabolismo , Dexametasona/farmacologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Glucocorticoides/farmacologia , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Cloreto de Metacolina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Neutrófilos/metabolismo , Oxidantes Fotoquímicos/farmacologia , Ozônio/farmacologia , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia
14.
J Immunol ; 172(4): 2549-58, 2004 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-14764728

RESUMO

The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8(+) T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8(+) T cells in the development of these allergen-induced responses. CD8-deficient (CD8(-/-)) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type mice, CD8(-/-) mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8(-/-) mice with allergen-sensitized CD8(+) T cells fully restored the development of AHR, BAL eosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8(+) T cells or allergen-sensitized CD8(+) T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8(+) T cells were a source of IL-13. These data suggest that Ag-primed CD8(+) T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells.


Assuntos
Antígenos/administração & dosagem , Hiper-Reatividade Brônquica/imunologia , Linfócitos T CD8-Positivos/imunologia , Interleucina-13/fisiologia , Pulmão/patologia , Ovalbumina/imunologia , Administração por Inalação , Transferência Adotiva , Animais , Antígenos/imunologia , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Antígenos CD8/genética , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Divisão Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Citocinas/metabolismo , Feminino , Imunoglobulina E/biossíntese , Inflamação/genética , Inflamação/imunologia , Injeções Intraperitoneais , Interleucina-13/biossíntese , Interleucina-13/deficiência , Interleucina-13/genética , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/administração & dosagem
15.
J Allergy Clin Immunol ; 112(6): 1078-87, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14657862

RESUMO

BACKGROUND: IL-13 is a central mediator of allergen-induced airway hyperresponsiveness (AHR), but its role in respiratory syncytial virus (RSV)-induced AHR is not defined. The combination of allergen exposure and RSV infection is known to increase AHR and lung inflammation, but whether IL-13 regulates this increase is similarly not known. OBJECTIVE: Our objective was to determine the role of RSV infection and IL-13 on airway responsiveness and lung inflammation on sensitized and challenged mice. METHODS: Using a murine model of RSV infection and allergen exposure, we examined the role of IL-13 in the development of AHR and lung inflammation in IL-13 knockout mice, as well as using a potent IL-13 inhibitor (IL-13i). Mice were sensitized and challenged to allergen, and 6 days after the last challenge, they were infected with RSV. IL-13 was inhibited using an IL-13 receptor alpha(2)-human IgG fusion protein. AHR to inhaled methacholine was measured 6 days after infection, as was bronchoalveolar lavage fluid and lung inflammatory and cytokine responses. RESULTS: RSV-induced AHR was unaffected by the IL-13i, despite prevention of goblet cell hyperplasia. Similar results were seen in IL-13-deficient mice. In sensitized and challenged mice, RSV infection significantly increased AHR, and after IL-13i treatment, AHR was significantly reduced, but to the levels seen in RSV-infected mice alone. CONCLUSIONS: These results indicate that despite some similarities, the mechanisms leading to AHR induced by RSV are different from those that follow allergen sensitization and challenge. Because IL-13 inhibition is effective in preventing the increases in AHR and mucus production in sensitized and challenged mice infected with RSV, IL-13i could play an important role in preventing the consequences of viral infection in patients with allergic asthma.


Assuntos
Alérgenos/imunologia , Hiper-Reatividade Brônquica/etiologia , Interleucina-13/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/patogenicidade , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-13/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Infecções por Vírus Respiratório Sincicial/virologia
16.
Am J Respir Crit Care Med ; 168(11): 1333-41, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14500265

RESUMO

Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but before allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness. To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor complement receptor-related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classic and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (Days 1 and 14) and challenged (Days 24-26) with ovalbumin. Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization before allergen challenge. Crry-Ig significantly prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia as well as the numbers of lung lymphocytes, decreased levels of interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and decreased serum ovalbumin-specific IgE and IgG1. These results suggest that prevention of complement activation may have a therapeutic role in the treatment of allergic airway inflammation and asthma in sensitized individuals.


Assuntos
Via Alternativa do Complemento/efeitos dos fármacos , Via Clássica do Complemento/efeitos dos fármacos , Imunoglobulina G/administração & dosagem , Proteínas/administração & dosagem , Receptores de Complemento/administração & dosagem , Hipersensibilidade Respiratória/tratamento farmacológico , Animais , Testes de Provocação Brônquica , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Complemento 3b
17.
Am J Respir Crit Care Med ; 168(7): 783-9, 2003 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12882759

RESUMO

The lung collectin surfactant protein D (SP-D) is an important component of the innate immune response but is also believed to play a role in other regulatory aspects of immune and inflammatory responses within the lung. The role of SP-D in the development of allergen-induced airway inflammation and hyperresponsiveness (AHR) is not well defined. SP-D levels progressively increased up to 48 hours after allergen challenge of sensitized mice and then subsequently decreased. The levels of SP-D paralleled the development of airway eosinophilia and AHR. To determine if this association was functionally relevant, mice were administered rat SP-D (rSP-D) intratracheally. When given to sensitized mice before challenge, AHR and eosinophilia were reduced by rSP-D in a dose-dependent manner but not by mutant rSP-D. rSP-D administration resulted in increased levels of interleukin (IL)-10, IL-12, and IFN-gamma in bronchoalveolar lavage fluid and reduced goblet cell hyperplasia. Culture of alveolar macrophages together with SP-D and allergen resulted in increased production of IL-10, IL-12, and IFN-gamma. These results indicate that SP-D can (negatively) regulate the development of AHR and airway inflammation after airway challenge of sensitized mice, at least in part, by modulating the function of alveolar macrophages.


Assuntos
Asma/prevenção & controle , Hiper-Reatividade Brônquica/prevenção & controle , Proteína D Associada a Surfactante Pulmonar/uso terapêutico , Surfactantes Pulmonares/uso terapêutico , Animais , Asma/metabolismo , Asma/fisiopatologia , Hiper-Reatividade Brônquica/etiologia , Hiper-Reatividade Brônquica/metabolismo , Testes de Provocação Brônquica , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Citocinas/metabolismo , Feminino , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Proteína D Associada a Surfactante Pulmonar/metabolismo , Proteína D Associada a Surfactante Pulmonar/farmacologia , Surfactantes Pulmonares/farmacologia
18.
J Immunol ; 170(8): 4301-9, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12682266

RESUMO

Following allergen challenge of sensitized mice, neutrophils are the first inflammatory cells found in bronchoalveolar lavage (BAL) fluid. To determine the underlying mechanism for their accumulation, mice were sensitized to OVA on days 0 and 14, and received, on day 28, a single intranasal challenge (s.i.n.) with either OVA or ragweed. Eight hours after the s.i.n., BAL fluid was obtained. BALB/c mice sensitized and challenged with OVA showed significantly higher total cell counts and numbers of neutrophils in BAL fluid compared to the OVA-sensitized and ragweed-challenged or nonsensitized mice. Levels of neutrophil chemokines in BAL fluid supernatants were markedly elevated in the sensitized and OVA-challenged mice; Fc epsilon RI-deficient mice showed comparable numbers of neutrophils and neutrophil chemokines in BAL fluid after s.i.n. But in sensitized mice lacking the Fc common gamma-chain and B cell-deficient mice, the number of neutrophils and levels of neutrophil chemokines in BAL fluid were significantly lower. Further, mice lacking the FcgammaRIII did not develop this early neutrophil influx. Neutrophil infiltration could be induced in naive mice following intranasal instillation of allergen combined with allergen-specific IgG1. In addition, macrophages from sensitized mice were stimulated with allergen and activated to produce neutrophil chemokines. These results demonstrate that neutrophil influx after allergen challenge requires prior sensitization, is allergen-specific, is mediated through FcgammaRIII, and is dependent on the presence of Ab.


Assuntos
Alérgenos/administração & dosagem , Alérgenos/imunologia , Especificidade de Anticorpos , Imunoglobulina E/fisiologia , Imunoglobulina G/fisiologia , Infiltração de Neutrófilos/imunologia , Receptores de IgG/fisiologia , Administração Intranasal , Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Agamaglobulinemia/patologia , Ambrosia/imunologia , Animais , Especificidade de Anticorpos/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Células Cultivadas , Quimiocinas/sangue , Quimiocinas/metabolismo , Epitopos/imunologia , Feminino , Imunização , Imunoglobulina G/metabolismo , Linfopenia/genética , Linfopenia/imunologia , Linfopenia/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores de IgG/deficiência , Receptores de IgG/genética
19.
J Immunol ; 169(11): 6482-9, 2002 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-12444158

RESUMO

The effectiveness of targeting IL-13 in models where airway hyperresponsiveness (AHR) and airway inflammation have already been established is not well-described. We investigated the effects of blocking IL-13 on the early and late phase airway responses and the development of AHR in previously sensitized and challenged mice. BALB/cByJ mice were sensitized (days 1 and 14) and challenged (days 28-30) with OVA. Six weeks later (day 72), previously sensitized/challenged mice were challenged with a single OVA aerosol and the early and late phase response and development of AHR were determined. Specific in vivo blockade of IL-13 was attained after i.p. injection of a soluble IL-13Ralpha2-IgG fusion protein (sIL-13Ralpha2Fc) on days 71-72 for the early and late responses and on days 71-73 for the development of AHR. sIL-13Ralpha2Fc administration inhibited the late, but not early, phase response and the OVA challenge-induced changes in lung resistance and dynamic compliance; as well, sIL-13Ralpha2Fc administration decreased bronchoalveolar lavage eosinophilia and mucus hypersecretion following the secondary challenge protocols. These results demonstrate that targeting IL-13 alone regulates airway responses when administrated to mice with established allergic airway disease. These data identify the importance of IL-13 in the development of allergen-induced altered airway responsiveness following airway challenge, even when administered before rechallenge of mice in which allergic disease had been previously established.


Assuntos
Interleucina-13/fisiologia , Hipersensibilidade Respiratória/imunologia , Resistência das Vias Respiratórias , Alérgenos/administração & dosagem , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/biossíntese , Feminino , Células Caliciformes/patologia , Hiperplasia , Fragmentos Fc das Imunoglobulinas/farmacologia , Imunoglobulinas/biossíntese , Inflamação/patologia , Interleucina-13/antagonistas & inibidores , Complacência Pulmonar , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Receptores de Interleucina , Proteínas Recombinantes de Fusão/farmacologia , Hipersensibilidade Respiratória/etiologia , Hipersensibilidade Respiratória/patologia , Hipersensibilidade Respiratória/fisiopatologia , Fatores de Tempo
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