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

Krug, Norbert; Hohlfeld, Jens M.; Kirsten, Anne-Marie; Kornmann, Oliver; Beeh, Kai Michael; Kappeler, Dominik; Korn, Stephanie; Ignatenko, Stanislav; Timmer, Wolfgang; Rogon, Cordelia; Zeitvogel, Jana; Zhang, Nan; Bille, Joachim; Homburg, Ursula; Turowska, Agnieszka; Bachert, Claus; Werfel, Thomas; Buhl, Roland; Renz, Jonas; Garn, Holger; Renz, Harald

doi:10.1056/nejmoa1411776

Cited by 276 publications

(202 citation statements)

References 42 publications

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“…As GATA3 expression is induced in patients with active ulcerative colitis and correlates with T H 2 and T H 9 cytokine levels in this disease, these observations indicate that GATA3 might be targeted for therapy of ulcerative colitis in humans. Indeed, GATA3 DNAzyme therapy has been successfully tested in patients with asthma 123 , a chronic inflammatory dis order of the airways associated with type 2 T helper (T H 2) cytokine production.…”

Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

485

375

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Inflammatory bowel diseases (including IBD, exempli fied by Crohn's disease and ulcerative colitis) are chronic relapsing disorders affecting the gastrointestinal tract. IBD has a progressive and destructive nature and, there fore, can cause various complications including steno ses, abscesses, fistulas, extraintestinal manifestations and colitis associated neoplasias and cancer 1,2 . Thus, effective therapeutic approaches are of high clinical rele vance in patients with IBD. This Review summarizes current therapeutic strategies and highlights emerging new treatment approaches for IBD with special refer ence to the proposed molecular mechanisms of action of anti inflammatory drugs. Current IBD therapiesClassic anti-inflammatory drugs. 5 Aminosalicylates (5 ASAs) are important anti inflammatory drugs that are frequently used for anti inflammatory therapy in patients with ulcerative colitis 3 . By contrast, 5 ASA based drugs show little or no efficacy in inducing res olution of clinical symptoms and tissue inflammation in patients with Crohn's disease 4 .5 ASAs are effective for induction and mainten ance of remission in ulcerative colitis and might also reduce the risk of developing colitis associated tumours in these patients 5 . Several mechanisms of action for 5 ASAs have been proposed, including reduction of prostaglandin synthesis via inhibition of cyclooxygenase, suppression of proinflammatory cytokine production and oxygen free radicals, inhib ition of lipoxygenase, blockade of neutrophil chemo taxis and mast cell activation, and impairment of nuclear factor κB activation (NF κB) in immune cells 3 . Moreover, studies in mice revealed that 5 ASA based drugs augment peroxisome proliferator activated receptor γ (PPARγ) expression and promote PPARγ translocation from the cytoplasm to the nucleus where they result in activation of peroxisome proliferator hormone response element driven genes to suppress colitis activity 6,7 .In addition to 5 ASAs, corticosteroids (systemically or topically delivered) have been used for remission induction in ulcerative colitis 2 . Although cortico steroids favour induction of remission in both ulcer ative colitis and Crohn's disease, they are not suitable for mainten ance of remission in IBD 1,2 . Mechanistically, gluco corticoids bind to a specific cytosolic receptor fol lowed by translocation of the complex to the nucleus to either activate or repress gene transcription (via bind ing to DNA corticosteroid response elements) 8,9 . Additionally, the glucocorticoid-receptor complex can inactivate pro inflammatory transcription factors such as NF κB and activator protein 1 (AP1) via proteinprotein inter actions, thereby preventing their activation of inflammatory mediators (for example, leukotrienes and cytokines such as IL 1 and IL 6). REVIEWS© 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Section: T Cellmentioning

confidence: 99%

Current and emerging therapeutic targets for IBD

Neurath

2017

Nat Rev Gastroenterol Hepatol

485

375

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“…Indeed, direct blockade of GATA-3 resulted in decreased early and late responses in patients with allergic asthma following allergen challenge. 4 In recent years, there has also been increasing attention to the role of the airway epithelium in mediating the inflammatory responses in the airways. It is now well recognized that epithelial-derived mediators such as TLSP and IL-33 are critically involved in the development and chronicity of allergic airway disease.…”

mentioning

confidence: 99%

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Reuter

Beckert

Taube

2016

Laboratory Investigation

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Bronchial asthma and chronic obstructive pulmonary disease (COPD) are chronic diseases that are associated with inflammation and structural changes in the airways and lungs. Recent findings have implicated Wnt pathways in critically regulating inflammatory responses, especially in asthma. Furthermore, canonical and noncanonical Wnt pathways are involved in structural changes such as airway remodeling, goblet cell metaplasia, and airway smooth muscle (ASM) proliferation. In COPD, Wnt pathways are not only associated with structural changes in the airways but also involved in the development of emphysema. The present review summarizes the role and function of the canonical and noncanonical Wnt pathway with regard to airway inflammation and structural changes in asthma and COPD. Further identification of the role and function of different Wnt molecules and pathways could help to develop novel therapeutic options for these diseases.

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“…The expression and the production of Th2 cytokines are also controlled by the transcription factor human GATA binding protein 3 (GATA3), which is necessary for the differentiation of Th2 lymphocytes. Applied in an asthma model in humans, GATA3-specific DNAzyme, a DNA molecule that destroys GATA3 RNA, led to the reduction in Th2 inflammation (81). In the upper airways, the monoclonal antibodies mepolizumab, reslizumab, omalizumab, and dupilumab have been subjected to proof-of-concept studies.…”

Section: Ways To Block Type 2 Responses In Allergic Airway Diseasementioning

confidence: 99%

Viruses and bacteria in Th2‐biased allergic airway disease

Feng

Zhang

Gevaert

et al. 2016

Allergy

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Allergic airway diseases are typically characterized by a type 2-biased inflammation. Multiple distinct viruses and bacteria have been detected in the airways. Recently, it has been confirmed that the microbiome of allergic individuals differs from that of healthy subjects, showing a close relationship with the type 2 response in allergic airway disease. In this review, we summarize the recent findings on the prevalence of viruses and bacteria in type 2-biased airway diseases and on the mechanisms employed by viruses and bacteria in propagating type 2 responses. The understanding of the microbial composition and postinfectious immune programming is critical for the reconstruction of the normal microflora and immune status in allergic airway diseases.

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

Cited by 276 publications

References 42 publications

Current and emerging therapeutic targets for IBD

Current and emerging therapeutic targets for IBD

Take the Wnt out of the inflammatory sails: modulatory effects of Wnt in airway diseases

Viruses and bacteria in Th2‐biased allergic airway disease

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