Molecular targets on mast cells and basophils for novel therapies

Harvima, Ilkka T.; Levi‐Schaffer, Francesca; Dráber, Petr; Friedman, Sheli; Polakovičová, Iva; Gibbs, Bernhard F.; Blank, Ulrich; Nilsson, Gunnar; Maurer, Marcus

doi:10.1016/j.jaci.2014.03.007

Cited by 124 publications

(122 citation statements)

References 235 publications

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“…Human mast cells are divided into TC-type (tryptase + and chymase + ), T-type (tryptase + ) and quite rare C-type (chymase + ) mast cells on the basis of their proteinase composition [6]. Both of these serine proteinases participate, for example, in inflammation and matrix remodeling (reviewed in Harvima et al [7]). The functions of mast cells in immune responses and allergy are well known [8].…”

Section: Introductionmentioning

confidence: 99%

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Siiskonen

Poukka

Bykachev³

et al. 2015

Melanoma Research

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The role of mast cells in cutaneous melanoma remains unclear. Tryptase and chymase are serine proteinases and major proteins in mast cell secretory granules. Therefore, this study aimed to investigate the presence of tryptase and chymase mast cells in benign and malignant cutaneous melanocytic lesions and in lymph node metastases of melanomas. The presence of positively stained mast cells was correlated with clinicopathological characteristics in invasive melanomas. Paraffin-embedded sections of 28 benign (13 intradermal, 10 compound, and five junctional nevi) and 26 dysplastic nevi, 15 in-situ melanomas, 36 superficially (pT1, Breslow's thickness<1 mm), and 49 deeply (pT4, Breslow's thickness>4 mm) invasive melanomas and 30 lymph node metastases were immunohistochemically stained for mast cell tryptase and chymase, and immunopositive cells were counted using the hotspot counting method. The mean count of tryptase and chymase mast cells was lower in invasive melanomas compared with in-situ melanomas and dysplastic and benign nevi. In deeply invasive melanomas, the difference was statistically significant compared with dysplastic nevi (P=0.003 for tryptase and P=0.009 for chymase) and in-situ melanomas (0.043 for tryptase). Low numbers of tryptase mast cells were associated with poor overall survival (P=0.031) in deeply invasive melanomas and with a more advanced stage (T1b, P=0.008) in superficially invasive melanomas. Low numbers of chymase mast cells were associated with microsatellites (P=0.017) in deeply invasive melanomas. The results suggest that these serine proteinases of mast cells may be protective in the pathogenesis of melanoma.

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Section: Introductionmentioning

confidence: 99%

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Siiskonen

Poukka

Bykachev³

et al. 2015

Melanoma Research

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“…Drugs that inhibit molecular targets upstream of Btk (SYK, PI3K) are also in development for asthma, allergic rhinitis, and rheumatoid arthritis, and have been recently reviewed. (27) RN983 is a potent (single digit nanomolar, Fig. 2), reversible, and selective Btk inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…(43) Btk inhibitors inhibit mast cells from generating a diverse number of mediators (13,44,45) that induce symptoms and the pathogenesis of asthma. (27) Both b-agonists and steroids are also known to have effects on mast cells. b-Agonists inhibit the release/generation FIG.…”

Section: Discussionmentioning

confidence: 99%

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

Phillips

Renteria

Burns

et al. 2016

Journal of Aerosol Medicine and Pulmonary Drug Delivery

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Background: In allergen-induced asthma, activated mast cells start the lung inflammatory process with degranulation, cytokine synthesis, and mediator release. Bruton's tyrosine kinase (Btk) activity is required for the mast cell activation during IgE-mediated secretion. Methods: This study characterized a novel inhaled Btk inhibitor RN983 in vitro and in ovalbumin allergic mouse models of the early (EAR) and late (LAR) asthmatic response. Results: RN983 potently, selectively, and reversibly inhibited the Btk enzyme. RN983 displayed functional activities in human cell-based assays in multiple cell types, inhibiting IgG production in B-cells with an IC 50 of 2.5 -0.7 nM and PGD 2 production from mast cells with an IC 50 of 8.3 -1.1 nM. RN983 displayed similar functional activities in the allergic mouse model of asthma when delivered as a dry powder aerosol by nose-only inhalation. RN983 was less potent at inhibiting bronchoconstriction (IC 50 (RN983) ¼ 59 lg/kg) than the bagonist salbutamol (IC 50 (salbutamol) ¼ 15 lg/kg) in the mouse model of the EAR. RN983 was more potent at inhibiting the antigen induced increase in pulmonary inflammation (IC 50 (RN983) ¼ <3 lg/kg) than the inhaled corticosteroid budesonide (IC 50 (budesonide) ¼ 27 lg/kg) in the mouse model of the LAR. Conclusions: Inhalation of aerosolized RN983 may be effective as a stand-alone asthma therapy or used in combination with inhaled steroids and b-agonists in severe asthmatics due to its potent inhibition of mast cell activation.

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“…Understanding molecular features of specific receptors could provide insight into different disease phenotypes and the variable outcomes from targeted therapies. Similarly, Harvina et al 52 proposed that understanding methods to inhibit receptor activation on mast cells and basophils could lead to development of novel therapeutics toward different molecules on mast cells and basophils. Therefore a better understanding of biomarkers and markers of cell activation is a step toward individualizing treatment strategies.…”

Section: Biomarkersmentioning

confidence: 99%

Advances in pediatric asthma in 2014: Moving toward a population health perspective

Szefler¹

2015

Journal of Allergy and Clinical Immunology

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Molecular targets on mast cells and basophils for novel therapies

Cited by 124 publications

References 235 publications

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Low numbers of tryptase+ and chymase+ mast cells associated with reduced survival and advanced tumor stage in melanoma

Btk Inhibitor RN983 Delivered by Dry Powder Nose-only Aerosol Inhalation Inhibits Bronchoconstriction and Pulmonary Inflammation in the Ovalbumin Allergic Mouse Model of Asthma

Advances in pediatric asthma in 2014: Moving toward a population health perspective

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