Treatment of allergic asthma: Modulation of Th2 cells and their responses

Bošnjak, Berislav; Stelzmueller, Barbara; Erb, Klaus J.; Epstein, Michelle M.

doi:10.1186/1465-9921-12-114

Cited by 167 publications

(136 citation statements)

References 277 publications

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“…1 T cells (21) stimulate increased IgE production in B cells (22). WT mice demonstrated significantly elevated serum IgE in response to HDM ( Figure 3A) in addition to increased IL-5 and IL-13 content within the lung ( Figure 4B).…”

Section: Discussionmentioning

confidence: 99%

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

Hoffman¹,

Qian²,

Nolin³

et al. 2016

Am J Respir Cell Mol Biol

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Protein S-glutathionylation (PSSG) is an oxidant-induced posttranslational modification of protein cysteines that impacts structure and function. The oxidoreductase glutaredoxin-1 (Glrx1) under physiological conditions catalyzes deglutathionylation and restores the protein thiol group. The involvement of Glrx1/PSSG in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study, we examined the impact of genetic ablation of Glrx1 in the pathogenesis of house dust mite (HDM)-induced allergic airways disease in mice. Wild-type (WT) or Glrx1 2/2 mice were instilled intranasally with HDM on 5 consecutive days for 3 weeks. As expected, overall PSSG was increased in Glrx1 2/2 HDM mice as compared with WT animals. Total cells in bronchoalveolar lavage fluid were similarly increased in HDMtreated WT and Glrx1 2/2 mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils and macrophages but fewer eosinophils as compared with HDM-exposed WT mice. mRNA expression of the Th2-associated cytokines IL-13 and IL-6, as well as mucin-5AC (Muc5ac), was significantly attenuated in Glrx1 2/2 HDM-treated mice. Conversely, mRNA expression of IFN-g and IL-17A was increased in Glrx1 2/2 HDM mice compared with WT littermates. Restimulation of singlecell suspensions isolated from lungs or spleens with HDM resulted in enhanced IL-17A and decreased IL-5 production in cells derived from inflamed Glrx1 2/2 mice compared with WT animals. Finally, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1 2/2 mice compared with WT littermates. These results demonstrate that the Glrx1-PSSG axis plays a pivotal role in HDM-induced allergic airways disease in association with enhanced type 2 inflammation and restriction of IFN-g and IL-17A.Keywords: asthma; protein S-glutathionylation; IL-17A; IFN-g; neutrophils Clinical RelevanceThis study demonstrates that the protein S-glutathionylation (PSSG)-glutaredoxin redox axis controls the nature of adaptive immune and inflammatory responses in an experimental model of allergic airways disease in mice. This advances our understanding the role that oxidative processes play in allergic disease and provides a platform for targeting PSSG chemistry to combat allergic airways disease.

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Section: Discussionmentioning

confidence: 99%

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

Hoffman¹,

Qian²,

Nolin³

et al. 2016

Am J Respir Cell Mol Biol

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“…These studies combined suggest that a successful vaccine may be designed by either encapsulating the antigen inside of the particle or by adsorbing the antigen on to the surface of the particle. The shift in Th2-type response to Th1-dominant immunity during early disease has been shown to prevent allergic inflammatory responses and lung remodeling (52,53). In this study, analysis of BAL fluids (Fig.…”

Section: Discussionmentioning

confidence: 99%

Development of a Poly (lactic-co-glycolic acid) Particle Vaccine to Protect Against House Dust Mite Induced Allergy

Joshi

Adamcakova‐Dodd

Jing

et al. 2014

AAPS J

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Abstract. Poly(lactic-co-glycolic acid) (PLGA) particles carrying antigen and adjuvant is a promising vaccine system which has been shown to stimulate systemic antigen-specific immune responses. In this study, we investigated the relationship of (i) the sizes of PLGA particle and (ii) the presence of cytosinephosphate-guanine motifs (CpG), with the extent and type of immune response stimulated against Dermatophagoides pteronyssinus-2 (Der p2) antigen. Different sizes of PLGA particles encapsulating CpG were prepared using a double emulsion solvent evaporation method. Mice were vaccinated with Der p2 and different sizes of empty or CpG-loaded PLGA particles. Vaccinated mice were exposed to daily intranasal instillation of Der p2 for 10 days followed by euthanization to estimate leukocyte accumulation in bronchoalveolar lavage (BAL) fluids, antibody profiles, and airway hyperresponsiveness. PLGA particles showed a size-dependent decrease in the proportion of eosinophils found in BAL fluids. Mice vaccinated with the Der p2 coated on 9-μm-sized empty PLGA particles showed increased levels of IgE and IgG1 antibodies as well as increased airway hyperresponsiveness. All sizes of PLGA particles encapsulating CpG prevented airway hyperresponsiveness after Der p2 exposures. Inflammatory responses to Der p2 exposure were significantly reduced when smaller PLGA particles were used for vaccination. In addition, encapsulating CpG in PLGA particles increased IgG2a secretion. This study shows that the size of PLGA particles used for vaccination plays a major role in the prevention of house dust mite-induced allergy and that incorporation of CpG into the PLGA particles preferentially develops a Th1-type immune response.

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“…Additionally, we and others have previously demonstrated that the Th2 master transcription factor GATA-3 and Th2 cytokines IL-4 and IL-13 are positively regulated at the posttranscriptional level by HuR (21)(22)(23). Therefore, we hypothesized that HuR is coordinately regulating Th2 polarization and cytokine secretion, implicating its involvement in Th2-mediated diseases, such as allergic airway inflammation (24,25).…”

Section: Introductionmentioning

confidence: 99%

Conditional Knockout of the RNA-Binding Protein HuR in CD4+ T Cells Reveals a Gene Dosage Effect on Cytokine Production

Gubin

Techasintana

Magee

et al. 2014

Mol Med

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The posttranscriptional mechanisms by which RNA binding proteins (RBPs) regulate T-cell differentiation and cytokine production in vivo remain unclear. The RBP HuR binds to labile mRNAs, usually leading to increases in mRNA stability and/or translation. Previous work demonstrated that HuR binds to the mRNAs encoding the Th2 transcription factor trans-acting T-cell-specific transcription factor (GATA-3) and Th2 cytokines interleukin (IL)-4 and IL-13, thereby regulating their expression. By using a novel conditional HuR knockout (KO)

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Treatment of allergic asthma: Modulation of Th2 cells and their responses

Cited by 167 publications

References 277 publications

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

Development of a Poly (lactic-co-glycolic acid) Particle Vaccine to Protect Against House Dust Mite Induced Allergy

Conditional Knockout of the RNA-Binding Protein HuR in CD4+ T Cells Reveals a Gene Dosage Effect on Cytokine Production

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