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1.
Clin Sci (Lond) ; 126(8): 567-80, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24152048

RESUMO

Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting ß2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C). Poly(I:C) alone induced a similar neutrophilic inflammatory profile in the BAL (bronchoalveolar lavage) to that of HRV1b (human rhinovirus 1b) alone, accompanied by both elevated BAL KC (keratinocyte-derived chemokine) and IL-1ß (interleukin-1ß). When mice allergic to HDM were also challenged with poly(I:C) the neutrophilic inflammatory profile was exacerbated. Increased CD8(+) T-cell numbers, increased CD4(+) and CD8(+) cell activation and elevated KC and IL-1ß were observed. No increases in Th2 cytokines or the eosinophil chemoattractant CCL11 [chemokine (C-C motif) ligand 11], above those induced by HDM alone, were observed. The poly(I:C)-exacerbated neutrophilia did not translate into changes in AHR (airways hyper-responsiveness), indicating that in this model inflammation and AHR are two mechanistically independent events. To test the clinical relevance of this model CS sensitivity was assessed using prednisone, a synthetic oral CS used to manage exacerbations in asthmatic patients already on maximal doses of inhaled CS. The increased neutrophils, and accompanying cytokines/chemokines KC and IL-1ß induced by poly(I:C) challenge of HDM-sensitized and challenged mice were insensitive to oral prednisone therapy. In summary we have described a CS-resistant mouse model mimicking the key aspects of viral asthma exacerbation using the clinically relevant aeroallergen HDM and the viral mimic poly(I:C). This model may provide better understanding of disease mechanisms underlying viral exacerbations and could be used to build early confidence in novel therapeutic axes targeting viral asthma exacerbations in Th2 asthmatics.


Assuntos
Asma/imunologia , Modelos Animais de Doenças , Infecções por Picornaviridae/imunologia , Rhinovirus/imunologia , Animais , Asma/tratamento farmacológico , Asma/virologia , Hiper-Reatividade Brônquica/imunologia , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocinas/imunologia , Feminino , Glucocorticoides/uso terapêutico , Células HeLa , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-1beta/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/imunologia , Infecções por Picornaviridae/virologia , Pneumonia/imunologia , Poli I-C/imunologia , Prednisona/uso terapêutico , Pyroglyphidae/imunologia , Rhinovirus/fisiologia , Receptor 3 Toll-Like/imunologia
2.
MAbs ; 7(1): 129-37, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25523454

RESUMO

Immunization of mice or rats with a "non-self" protein is a commonly used method to obtain monoclonal antibodies, and relies on the immune system's ability to recognize the immunogen as foreign. Immunization of an antigen with 100% identity to the endogenous protein, however, will not elicit a robust immune response. To develop antibodies to mouse proteins, we focused on the potential for breaking such immune tolerance by genetically fusing two independent T-cell epitope-containing sequences (from tetanus toxin (TT) and diphtheria toxin fragment A (DTA)) to a mouse protein, mouse ST2 (mST2). Wild-type CD1 mice were immunized with three mST2 tagged proteins (Fc, TT and DTA) and the specific serum response was determined. Only in mice immunized with the T-cell epitope-containing antigens were specific mST2 serum responses detected; hybridomas generated from these mice secreted highly sequence-diverse IgGs that were capable of binding mST2 and inhibiting the interaction of mST2 with its ligand, mouse interleukin (IL)-33 (mIL-33). Of the hundreds of antibodies profiled, we identified five potent antibodies that were able to inhibit IL-33 induced IL-6 release in a mast cell assay; notably one such antibody was sufficiently potent to suppress IL-5 release and eosinophilia infiltration in an Alternaria alternata challenge mouse model of asthma. This study demonstrated, for the first time, that T-cell epitope-containing tags have the ability to break tolerance in wild-type mice to 100% conserved proteins, and it provides a compelling argument for the broader use of this approach to generate antibodies against any mouse protein or conserved ortholog.


Assuntos
Anticorpos Monoclonais Murinos/imunologia , Especificidade de Anticorpos , Epitopos de Linfócito T/imunologia , Receptores de Interleucina/imunologia , Animais , Anticorpos Monoclonais Murinos/farmacologia , Asma/tratamento farmacológico , Asma/imunologia , Asma/patologia , Linhagem Celular Transformada , Toxina Diftérica/química , Toxina Diftérica/imunologia , Epitopos de Linfócito T/química , Feminino , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Receptores de Interleucina/química , Toxina Tetânica/química , Toxina Tetânica/imunologia
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