Trials and tribulations in identifying new biologic treatments for asthma

Holgate, Stephen T.

doi:10.1016/j.it.2012.02.003

Cited by 41 publications

(23 citation statements)

References 105 publications

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“…7 Thus, interventions that can disrupt this immune network -including treatments targeting components downstream of the transcription factor GATA3 -are being developed for the treatment of asthma. 8 Since GATA3 is expressed only in intracellular processes, we developed a GATA3-specific DNA enzyme (DNAzyme) with in vivo cell-penetrating capabilities. DNAzymes are catalytically active, single-stranded, synthetic DNA antisense molecules that do not occur in nature.…”

mentioning

confidence: 99%

Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

et al. 2015

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confidence: 99%

Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

et al. 2015

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“…6,[18][19][20][21][22][23][24] Epithelial cell-derived IL-33, induced by airborne allergens, viruses, and air pollutants, is known to activate naïve and Th2 lymphocytes, mast cells, and eosinophils and promotes Th2-type cytokine production via a ST2, a membrane-bound IL-33-specific receptor expressed on mast cells, Th2 cells, and eosinophils. 20 Therefore, we evaluated whether conjunctival CD4 þ T cells in our murine model of allergic conjunctivitis expressed ST2 and produced IL-5 on repeated allergen challenge.…”

Section: St2mentioning

confidence: 99%

“…4,5 Recent studies have highlighted the IL-33-ST2 interaction pathway as a potential target in allergic disease. [18][19][20][21][22][23][24] ST2 is an orphan receptor, an IL-1 receptor family member that is also known to be expressed on murine Th2 and mast cells and binds with the ligand IL-33. 18 CD4 þ T cells become ST2 þ on repeated antigenic stimulation under Th2-polarizing conditions, but in an IL-4-independent mechanism, and the crosslinking of IL-33 and ST2 induces proliferation and cytokine production in Th2, but not Th1, cells.…”

Section: Figurementioning

confidence: 99%

Development of Allergic Conjunctivitis Induced by House Dust Mite Extract FromDermatophagoides pteronyssinus

Lee

Han

Lee

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to develop a murine model of allergic conjunctivitis induced by house dust mite (HDM) extract from Dermatophagoides pteronyssinus, a major allergen in humans.METHODS. Forty BALB/c mice were divided into five groups, immunized with placebo, ovalbumin (10 lg), or HDM extract following a schedule. Twenty minutes after topical challenge, mice were examined clinically. Material collected from mice was used for measuring total and specific IgE, antigen-specific lymphocyte proliferation, and supernatant cytokine levels and for conjunctival histopathology and flow cytometric analysis of conjunctival cells.RESULTS. This murine model showed similar clinical signs and laboratory findings to human allergy and the ovalbumin-induced allergic conjunctivitis model. Total IgE levels and conjunctival infiltration of mast cells and eosinophils in immunized mice were significantly higher than in the control group. Cervical lymphocyte proliferation was increased in antigenstimulated cultures in immunized mice, concomitant with significantly higher IL-4 and IL-5 levels in the culture supernatant. The proportion of conjunctival CD4 þ T cells expressing the ST2 receptor was increased, and conjunctival CD4 þ ST2þ T cells exhibited an increase in intracellular IL-5.CONCLUSIONS. House dust mite extract successfully induced allergic conjunctivitis in BALB/c mice. Ten micrograms of HDM extract was the optimal dose for systemic immunization in this model. This murine model is suitable for further studies on HDM-induced allergic conjunctivitis, and the data show that conjunctival CD4 þ T cells expressing ST2 may play an important role in IL-5 secretion, recruiting eosinophils into conjunctiva on ocular allergen challenge.

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“…The mechanism of how eosinophilic disease may modulate exacerbations in asthma remains unknown. Furthermore, non-eosinophilic phenotypes of asthma are common in the general population and new therapies targeting non-type 2 helper T-cell pathways (reviewed in [12]) and bronchial smooth muscle lability (bronchial thermoplasty; [13]) are emerging. These therapies are unlikely to show efficacy in every patient with asthma and will probably need to be personalized by patient phenotype informed by an understanding of the interactions between different scales of the disease.…”

Section: The Need For Multi-scale Models Of the Respiratory Systemmentioning

confidence: 99%

Multi-scale computational models of the airways to unravel the pathophysiological mechanisms in asthma and chronic obstructive pulmonary disease (AirPROM)

et al. 2013

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Biomax Informatics AG, Munich, GermanyThe respiratory system comprises several scales of biological complexity: the genes, cells and tissues that work in concert to generate resultant function. Malfunctions of the structure or function of components at any spatial scale can result in diseases, to the detriment of gas exchange, right heart function and patient quality of life. Vast amounts of data emerge from studies across each of the biological scales; however, the question remains: how can we integrate and interpret these data in a meaningful way? Respiratory disease presents a huge health and economic burden, with the diseases asthma and chronic obstructive pulmonary disease (COPD) affecting over 500 million people worldwide. Current therapies are inadequate owing to our incomplete understanding of the disease pathophysiology and our lack of recognition of the enormous disease heterogeneity: we need to characterize this heterogeneity on a patient-specific basis to advance healthcare. In an effort to achieve this goal, the AirPROM consortium (Airway disease Predicting Outcomes through patient-specific computational Modelling) brings together a multidisciplinary team and a wealth of clinical data. Together we are developing an integrated multi-scale model of the airways in order to unravel the complex pathophysiological mechanisms occurring in the diseases asthma and COPD.

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Trials and tribulations in identifying new biologic treatments for asthma

Cited by 41 publications

References 105 publications

Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

Allergen-Induced Asthmatic Responses Modified by a GATA3-Specific DNAzyme

Development of Allergic Conjunctivitis Induced by House Dust Mite Extract FromDermatophagoides pteronyssinus

Multi-scale computational models of the airways to unravel the pathophysiological mechanisms in asthma and chronic obstructive pulmonary disease (AirPROM)

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