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1.
Am J Pathol ; 179(1): 104-15, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21640974

RESUMEN

IL-33 and its soluble receptor and cell-associated receptor (ST2L) are all increased in clinical and experimental asthma. The present study addressed the hypothesis that ST2L impairs the therapeutic effects of CpG in a fungal model of asthma. C57BL/6 mice were sensitized to Aspergillus fumigatus and challenged via i.t. instillation with live A. fumigatus conidia. Mice were treated with IgG alone, anti-ST2L monoclonal antibody (mAb) alone, CpG alone, IgG plus CpG, or anti-ST2L mAb plus CpG every other day from day 14 to day 28 and investigated on day 28 after conidia. Lung ST2L and toll-like receptor 9 protein expression levels concomitantly increased in a time-dependent manner during fungal asthma. Therapeutic blockade of ST2L with an mAb attenuated key pathological features of this model. At subtherapeutic doses, neither anti-ST2L mAb nor CpG alone affected fungal asthma severity. However, airway hyperresponsiveness, mucus cell metaplasia, peribronchial fibrosis, and fungus retention were markedly reduced in asthmatic mice treated with the combination of both. Whole lung CXCL9 levels were significantly elevated in the combination group but not in the controls. Furthermore, in asthmatic mice treated with the combination therapy, dendritic cells generated significantly greater IL-12p70 with CpG in vitro compared with control dendritic cells. The combination of anti-ST2L mAb with CpG significantly attenuated experimental asthma, suggesting that targeting ST2L might enhance the therapeutic efficacy of CpG during allergic inflammation.


Asunto(s)
Aspergilosis Broncopulmonar Alérgica/prevención & control , Asma/prevención & control , Pulmón/efectos de los fármacos , Oligodesoxirribonucleótidos/uso terapéutico , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/fisiología , Animales , Anticuerpos Monoclonales/uso terapéutico , Aspergilosis Broncopulmonar Alérgica/inmunología , Aspergilosis Broncopulmonar Alérgica/microbiología , Aspergillus fumigatus/inmunología , Aspergillus fumigatus/metabolismo , Asma/microbiología , Western Blotting , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/microbiología , Hiperreactividad Bronquial/prevención & control , Estudios de Casos y Controles , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Enfermedad Crónica , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibrosis/prevención & control , Humanos , Técnicas para Inmunoenzimas , Inmunoglobulina G/uso terapéutico , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo
2.
Immunol Invest ; 40(7-8): 692-722, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21592044

RESUMEN

Triggering receptor expressed on myeloid cells-1 (TREM-1) expression is increased during pulmonary fungal infection suggesting that this receptor might be involved in anti-fungal immune responses. To address the role of TREM-1 in a murine model of fungal allergic airway disease, A. fumigatus-sensitized CBA/J mice received by intratracheal injection a mixture of live A. fumigatus conidia and one of a control adenovirus vector (Ad70), an adenovirus containing a gene encoding for the extracellular domain of mouse TREM-1 and the F(c) portion of human IgG (AdTREM-1Ig; a soluble inhibitor of TREM-1 function), or an adenovirus containing mouse DAP12 (AdDAP12; DAP12 is an intracellular adaptor protein required for TREM-1 signaling), and examined at various days after challenge. Whole lung TREM-1 levels peaked at day 3 whereas circulating TREM-1 levels peaked at day 30 in this fungal asthma model. AdTREM-1Ig-treated mice exhibited significantly higher airway hyperresponsiveness following methacholine challenge compared with Ad70- and AdDAP12-treated mice. Whole lung analysis of AdTREM-1Ig treated mice revealed markedly higher amounts of fungal material compared with the other groups. ELISA analysis of whole lung and bronchoalveolar lavage samples indicated that several pro-allergic cytokine and chemokines including CCL17 and CCL22 were significantly increased in the AdTREM-1Ig group compared with the other groups. Finally, Pam3Cys and soluble Aspergillus antigens induced TREM-1 transcript expression in macrophages in a TLR2 dependent manner. In conclusion, TREM-1 modulates the immune response directed against A. fumigatus during experimental fungal asthma.


Asunto(s)
Aspergilosis Broncopulmonar Alérgica/inmunología , Aspergillus fumigatus/patogenicidad , Asma/inmunología , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Aspergilosis Broncopulmonar Alérgica/microbiología , Aspergillus fumigatus/inmunología , Asma/microbiología , Hiperreactividad Bronquial , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocinas/biosíntesis , Quimiocinas/inmunología , Citocinas/biosíntesis , Citocinas/inmunología , Femenino , Humanos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Receptores Inmunológicos/genética , Receptor Activador Expresado en Células Mieloides 1
3.
Int Arch Allergy Immunol ; 152(2): 98-112, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20016192

RESUMEN

BACKGROUND: CpG administration abolishes airway inflammation and remodeling in acute models of allergic airway disease. METHODS: Herein, we investigated the therapeutic effect of CpG in a chronic fungal model of asthma. TLR9+/+ and TLR9-/- mice were sensitized to soluble Aspergillus fumigatus antigens and challenged with live A. fumigatus conidia. Mice were treated with intraperitoneal (IP) or intranasal (IN) CpG, or left untreated 14-28 days after conidium challenge. All features of allergic airway disease were attenuated in TLR9+/+ mice treated with IN CpG, including airway hyperresponsiveness (AHR), mucus production, and peribronchial fibrosis. RESULTS: TLR9-/- mice treated with IN CpG exhibited attenuated airway remodeling but not AHR. Whole-lung IL-12 levels were significantly elevated in both TLR9+/+ and TLR9-/- mice receiving IN CpG but not in either group receiving IP CpG. Whole-lung IL-10 levels were significantly elevated in IN CpG-treated TLR9+/+ mice but not in TLR9-/- mice receiving IN CpG. Increased whole-lung transcript and protein levels of the scavenger receptors SR-A and MARCO were observed in TLR9-/- mice compared with TLR9+/+ mice, possibly accounting for the CpG responsiveness in the knockout group. CONCLUSIONS: Together, these data show that IN CpG has a therapeutic effect during established fungal asthma, which is TLR9 dependent and independent.


Asunto(s)
Aspergillus fumigatus/inmunología , Asma/terapia , Oligodesoxirribonucleótidos/uso terapéutico , Receptor Toll-Like 9/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Administración Intranasal , Animales , Aspergillus fumigatus/patogenicidad , Asma/inmunología , Asma/microbiología , Asma/patología , Asma/fisiopatología , Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/terapia , Quimiocina CXCL10/genética , Citocinas/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Interferón-alfa/genética , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Moco/metabolismo , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/farmacología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/terapia , Receptores Inmunológicos/metabolismo , Receptores Depuradores de Clase A/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 9/genética
4.
Infect Immun ; 77(1): 108-19, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18936185

RESUMEN

The role of Toll-like receptor 9 (TLR9) in antifungal responses in the immunodeficient and allergic host is unclear. We investigated the role of TLR9 in murine models of invasive aspergillosis and fungal asthma. Neutrophil-depleted TLR9 wild-type (TLR9(+/+)) and TLR9-deficient (TLR9(-/-)) mice were challenged with resting or swollen Aspergillus fumigatus conidia and monitored for survival and lung inflammatory responses. The absence of TLR9 delayed, but did not prevent, mortality in immunodeficient mice challenged with resting or swollen conidia compared to TLR9(+/+) mice. In a fungal asthma model, TLR9(+/+) and TLR9(-/-) mice were sensitized to soluble A. fumigatus antigens and challenged with resting or swollen A. fumigatus conidia, and both groups of mice were analyzed prior to and at days 7, 14, and 28 after the conidium challenge. When challenged with resting conidia, TLR9(-/-) mice exhibited significantly lower airway hyper-responsiveness compared to the TLR9(+/+) groups. In contrast, A. fumigatus-sensitized TLR9(-/-) mice exhibited pulmonary fungal growth at days 14 and 28 after challenge with swollen conidia, a finding never observed in their allergic wild-type counterparts. Increased fungal growth in allergic TLR9(-/-) mice correlated with markedly decreased dectin-1 expression in whole lung samples and isolated dendritic cell populations. Further, whole lung levels of interleukin-17 were lower in allergic TLR9(-/-) mice compared to similar TLR9(+/+) mice. Together, these data suggest that TLR9 modulates pulmonary antifungal immune responses to swollen conidia, possibly through the regulation of dectin-1 expression.


Asunto(s)
Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Asma/inmunología , Esporas Fúngicas/inmunología , Receptor Toll-Like 9/inmunología , Animales , Femenino , Interleucina-17/análisis , Lectinas Tipo C , Pulmón/química , Pulmón/microbiología , Pulmón/patología , Proteínas de la Membrana/análisis , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Proteínas del Tejido Nervioso/análisis , Análisis de Supervivencia , Receptor Toll-Like 9/deficiencia
5.
Genesis ; 44(7): 336-44, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16823861

RESUMEN

Nestin-Cre mice are widely used to generate gene deletions in the developing brain. Surprisingly, fewNestin-Cre lines have been characterized for their temporal and brain region-specific recombination. In addition, some Nestin-Cre lines express Cre outside the central nervous system, making it difficult to choose appropriate lines for targeting genes with brain region-restricted expression. Here we describe the properties of a Nestin-Cre transgenic line and its use for conditional deletions of Pitx2, a paired-like homeodomain transcription factor. We report that Nestin-Cre conditional Pitx2 mutant mice have ocular and craniofacial defects consistent with the role of human PITX2 in Rieger syndrome. Conditional mutants exhibit defects in midbrain neuronal development similar to those in Pitx2 homozygous null embryos, but lack the abnormalities in subthalamic nucleus neurons that occur with complete loss of Pitx2 function. These data indicate that normal differentiation of midbrain neurons depends upon adequate Pitx2 function during the period of active neurogenesis.


Asunto(s)
Proteínas de Homeodominio/genética , Integrasas/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Eliminación de Secuencia , Animales , Encéfalo/embriología , Embrión de Mamíferos , Desarrollo Embrionario/genética , Femenino , Marcación de Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Nestina , Especificidad de Órganos/genética , Factores de Transcripción , Proteína del Homeodomínio PITX2
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