Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.

CysLT1 antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT1 antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C4 synthase (LTC4S) gene in Japanese patients with moderate asthma. The frequency of LTC4S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects (n = 349). A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400–800 μg/day or fluticasone 200–400 μg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes (n = 31) [14.3 ± 5.3% vs. 3.1 ± 2.4% improvement of forced expiratory volume in one second (FEV1), P < 0.01], while LTC4S genotype-stratified response to inhaled β-agonist salbutamol (200 μg) was not observed (17.5 ± 2.1% vs. 18.7 ± 2.2% improvement of FEV1). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV1) was correlated with LTC4S genotype (P < 0.01) and pretreatment airway reversibility to salbutamol (P < 0.01), but not with sex, age, atopic status, urinary leukotriene E4 excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC4S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P < 0.05). We conclude that LTC4S genotype is predictive of the clinical response to a cysLT1 antagonist, pranlukast, in Japanese patients with moderate asthma.

Asthma is a heterogeneous disease composed of various phenotypes. Periostin, a molecule inducible with interleukin (IL)-4 or IL-13 in bronchial epithelial cells, is a biomarker of "TH2-high" asthma. The objective of this study is to examine whether the serum periostin concentrations are correlated with the severity, specific phenotype(s), or comorbidity of asthma. Serum concentrations of periostin were measured in 190 Japanese asthmatic patients and 11 healthy controls. The protocol was registered under UMIN 000002980 in the clinical trial registry. The serum concentrations of periostin were significantly higher (P = 0.014) in asthmatics [70.0 (54.0-93.5) ng/ml] than in healthy subjects [57.0 (39.0-63.0) ng/ml], though we found no correlation between serum periostin concentrations and treatment steps required to control asthma. To characterize "high-periostin" phenotype(s), the patients with asthma were divided among tertiles based on the serum concentrations of periostin. The high-periostin group was older at onset of asthma (P = 0.04), had a higher prevalence of aspirin intolerance (P = 0.04) or concomitant nasal disorders (P = 0.03-0.001), higher peripheral eosinophil counts (P < 0.001), and lower pulmonary function (P = 0.02-0.07). The serum concentrations of periostin were particularly high in asthmatic patients complicated by chronic rhinosinusitis with nasal polyps and olfactory dysfunction. In contrast, neither atopic status, control status of asthma, nor quality of life were related with the "high-periostin" phenotype. Elevated periostin concentrations in serum were correlated with a specific phenotype of eosinophilic asthma, late-onset and often complicated by obstructive pulmonary dysfunction and nasal disorders.

TSLP is an epithelial cell-derived cytokine synthesized in response to various stimuli, including protease allergens and microorganisms like viruses and bacteria. Biological functions of TSLP require heterodimer formation between the TSLP receptor (TSLPR) and IL-7 receptor-α, which polarize dendritic cells to induce type 2 inflammation and directly expand and/or activate Th2 cells, group 2 innate lymphoid cells, basophils, and other immune cells. TSLP is thus considered a master regulator of type 2 immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. Indeed, genetic, experimental, and clinical evidence suggests that the TSLP-TSLPR pathway is associated with the pathogenesis of allergic diseases such as atopic dermatitis (AD) and asthma. Tezepelumab (AMG-157/MEDI9929) is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. A phase 2 trial for moderate to severe AD showed that a greater but not statistically significant percentage of tezepelumab-treated patients showed clinical improvements compared to the placebo group. A phase 2 trial for uncontrolled, severe asthma showed significant decreases in asthma exacerbation rate and improved pulmonary function and asthma control for tezepelumab-treated patients. Levels of biomarkers of type 2 inflammation, such as blood/sputum eosinophil counts and fraction of exhaled nitric oxide decreased, however, clinical efficacy was observed irrespective of the baseline levels of these biomarkers. A blockade of the TSLP-TSLPR pathway likely will exert significant clinical effects on AD, asthma, and other allergic diseases. The efficacy of anti-TSLP antibodies compared to other biologics needs to be further examined.

Mast cell-derived prostaglandin D₂ (PGD₂) is one of the essential modulators of eosinophilic airway inflammation in asthma and allergic rhinitis. Two G protein-coupled receptors for PGD₂, prostaglandin D₂ receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th₂ cells (CRTH2), are both expressed on the surface of eosinophils, and CRTH2 has been demonstrated to mediate PGD₂-induced eosinophil mobilization in vitro. However, it has not yet been determined whether PGD₂ and its receptors mediate in vivo eosinophil trafficking into the airways or other organs. We demonstrated that intratracheal administration of PGD₂ in rats pretreated with systemic interleukin-5 (IL-5) injection induced marked airway eosinophilia, determined by the differential counts of cells in bronchoalveolar lavage (BAL) fluid and lung histology, within 2 h. Systemic IL-5 alone significantly increased the number of eosinophils in the peripheral blood but showed no effect on airway eosinophilia. Three CRTH2-specific agonists (13,14-dihydro-15-keto-PGD₂, 11-deoxy-11-methylene-15-keto-PGD₂, and indomethacin) demonstrated equivalent induction of BAL eosinophilia to that of PGD₂, but a DP agonist (BW 245C [5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin]) or a thromboxane A₂ receptor (TP) agonist ([1S-1α,2β(5Z), 3α(1E,3R*),4α)]-7-[3-(3-hydroxy-4-(4′-iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-heptenoic acid) showed no effect. PGD₂ or CRTH2 agonist-induced BAL eosinophilia was almost completely inhibited by pretreatment with a CRTH2/TP antagonist, ramatroban [BAY-u3405; (+)-(3R)-3-(4-fluorobenzenesulfonamido)-1,2,3,4-tetra-hydrocarbazole-9-propionic acid], whereas a TP-specific antagonist, SQ29,548 (5-heptenoic, 7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-[1S-[1α,2α(Z),3α,4α]]), or a DP-specific antagonist, BW A868C [3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexy-2-hydroxyethylamino)-hydantoin], did not inhibit the effects of PGD₂. These results suggest that CRTH2 plays a significant role in the eosinophil trafficking from the bloodstream into the airways in PGD₂-related airway inflammation.