The Editors' Choice

Abstract

A new trick for an old dog?Syk kinase inhibition for allergic rhinitisAllergic rhinitis continues to be the most prevalent respiratory disorder in industrialized societies, increasing in incidence and affecting nearly a third of the adult population. Despite numerous effective therapies, many patients are left with suboptimal symptom control, and therapeutic options using different modes of action are desirable. Of considerable interest is the inhibition of IgE action, because IgE is the main trigger in allergic inflammation. In this issue, Rossi and colleagues (p 749) report the cellular and molecular characterization of R112, a novel small molecule inhibitor of IgE-receptor signaling in human mast cells and basophils. The authors show that R112 rapidly inhibits the activity of the tyrosine kinase Syk induced by the crosslinking of the IgE receptor, thereby blocking all downstream events dependent on Syk, which include mast cell degranulation and the production of lipid mediators and inflammatory cytokines. Significantly, these results correlate with data from a clinical study reported in a previous issue of the Journal, in which intranasal R112 produced rapid and significant improvements in an array of symptoms of allergic rhinitis in patients studied in a park environment. The investigators studying R112 provide initial molecular and cellular insights highlighting the potential beneficial effects of Syk inhibition as a treatment for allergic disorders. The development of local and systemic inhibitors of Syk kinase with appropriate pharmacokinetic and pharmaceutic properties may be an important therapeutic opportunity.Cysteinyl leukotrienes are important mediators of persistent disease in children with moderate/severe asthmaAlthough the use of leukotriene receptor antagonists improves disease control in children and adults with asthma, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly. In a study by Rabinovitch et al (p 635), 50 children, primarily with moderate-to-severe asthma, were followed by monitoring levels of urinary leukotriene E4 (LTE4), forced expiratory volume in 1 second (FEV1), and albuterol use. Levels of urinary LTE4 were directly associated with clinically significant declines in lung function and increased albuterol usage despite use of inhaled corticosteroids together with long-acting bronchodilators. This association was highest in children with persistent airway obstruction and was significantly blunted in children taking the cysteinyl leukotriene receptor 1 antagonist, montelukast. These data suggest that therapies designed to interfere with the activity of the cysteinyl leukotriene pathway may benefit children receiving inhaled corticosteroids and long-acting β-agonist therapy who continue to experience persistent disease.Cat and dust mite allergen levels in European homesIn never–cat-owners' homes, there is a significant correlation of community prevalence of cat ownership and level of cat allergen.View Large Image Figure ViewerDownload (PPT)Does CD14C-159T modulate the effect of farm exposure on allergy?A higher exposure to bacterial compounds—in particular, endotoxin—is purported to explain the lower prevalence of allergy in farm children. If early exposure to endotoxin may have a protective role, one might expect that genetic factors that modify endotoxin responsiveness would also influence the susceptibility to develop atopic diseases. In this issue of the Journal, Leynaert et al (p 658) investigate whether the effect of farm exposure on atopy is modulated by a CD14 promoter functional polymorphism. They analyzed data from 600 randomly selected young adults recruited in 2 French centers participating in the European Community Respiratory Health Survey. The results were consistent in the 2 centers. A lower risk of allergic rhinitis and atopy was observed in carriers of the CD14-159TT genotype as compared to -159CC subjects. Farm exposure in early life was also associated with a lower risk of nasal allergies and atopic sensitization in adulthood. However, the protective effect of farm exposure was slightly more marked in carriers of the -159TT genotype (adjusted odds ratio 0.42, and 0.24, respectively) than in -159CC+CT subjects. These findings are consistent with a gene-environment interaction whereby the CD14 C-159T would modulate the effect of environmental exposure on the development of atopy.Cat keeping, allergy, and asthmaThe relationship between pet exposure in childhood and the development of allergy and asthma continues to be unclear. It is plausible that exposure to pet allergens or microbial exposures associated with pet keeping is protective or, on the other hand, that there is selective avoidance of pets by subjects at risk for developing allergy and asthma. In this issue of the Journal, Svanes and coauthors (p 691) address this subject using data from 9812 subjects who participated in the European Community Respiratory Health Survey (ECRHS). Data were obtained when the subjects were 20-44 years of age (ECRHS I) and again an average of 9 years later (ECRHS II). Information on childhood asthma and pet keeping was retrospectively obtained at the first visit. Onset of asthma before age 5 years was associated with less cat keeping at 5-15 years (odds ratio [OR] = 0.60), an effect observed only when the parents did not have asthma or allergies. The onset of asthma up to age 15 years had no effect on subjects' pet keeping at the time of ECRHS I. Those with asthma and allergy, atopy, or cat-specific IgE at ECRHS I were less likely to have acquired a cat at follow-up (ECRHS II) but were no less likely to have retained one at ECRHS I. The authors conclude that selective avoidance subsequent to asthma or allergy was observed for childhood cat keeping and adult cat acquisition. Avoidance would produce an apparent “protective” effect of cats on childhood asthma. Avoidance was generally not observed for dogs or birds. A new trick for an old dog? Syk kinase inhibition for allergic rhinitisAllergic rhinitis continues to be the most prevalent respiratory disorder in industrialized societies, increasing in incidence and affecting nearly a third of the adult population. Despite numerous effective therapies, many patients are left with suboptimal symptom control, and therapeutic options using different modes of action are desirable. Of considerable interest is the inhibition of IgE action, because IgE is the main trigger in allergic inflammation. In this issue, Rossi and colleagues (p 749) report the cellular and molecular characterization of R112, a novel small molecule inhibitor of IgE-receptor signaling in human mast cells and basophils. The authors show that R112 rapidly inhibits the activity of the tyrosine kinase Syk induced by the crosslinking of the IgE receptor, thereby blocking all downstream events dependent on Syk, which include mast cell degranulation and the production of lipid mediators and inflammatory cytokines. Significantly, these results correlate with data from a clinical study reported in a previous issue of the Journal, in which intranasal R112 produced rapid and significant improvements in an array of symptoms of allergic rhinitis in patients studied in a park environment. The investigators studying R112 provide initial molecular and cellular insights highlighting the potential beneficial effects of Syk inhibition as a treatment for allergic disorders. The development of local and systemic inhibitors of Syk kinase with appropriate pharmacokinetic and pharmaceutic properties may be an important therapeutic opportunity. Allergic rhinitis continues to be the most prevalent respiratory disorder in industrialized societies, increasing in incidence and affecting nearly a third of the adult population. Despite numerous effective therapies, many patients are left with suboptimal symptom control, and therapeutic options using different modes of action are desirable. Of considerable interest is the inhibition of IgE action, because IgE is the main trigger in allergic inflammation. In this issue, Rossi and colleagues (p 749) report the cellular and molecular characterization of R112, a novel small molecule inhibitor of IgE-receptor signaling in human mast cells and basophils. The authors show that R112 rapidly inhibits the activity of the tyrosine kinase Syk induced by the crosslinking of the IgE receptor, thereby blocking all downstream events dependent on Syk, which include mast cell degranulation and the production of lipid mediators and inflammatory cytokines. Significantly, these results correlate with data from a clinical study reported in a previous issue of the Journal, in which intranasal R112 produced rapid and significant improvements in an array of symptoms of allergic rhinitis in patients studied in a park environment. The investigators studying R112 provide initial molecular and cellular insights highlighting the potential beneficial effects of Syk inhibition as a treatment for allergic disorders. The development of local and systemic inhibitors of Syk kinase with appropriate pharmacokinetic and pharmaceutic properties may be an important therapeutic opportunity. Cysteinyl leukotrienes are important mediators of persistent disease in children with moderate/severe asthmaAlthough the use of leukotriene receptor antagonists improves disease control in children and adults with asthma, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly. In a study by Rabinovitch et al (p 635), 50 children, primarily with moderate-to-severe asthma, were followed by monitoring levels of urinary leukotriene E4 (LTE4), forced expiratory volume in 1 second (FEV1), and albuterol use. Levels of urinary LTE4 were directly associated with clinically significant declines in lung function and increased albuterol usage despite use of inhaled corticosteroids together with long-acting bronchodilators. This association was highest in children with persistent airway obstruction and was significantly blunted in children taking the cysteinyl leukotriene receptor 1 antagonist, montelukast. These data suggest that therapies designed to interfere with the activity of the cysteinyl leukotriene pathway may benefit children receiving inhaled corticosteroids and long-acting β-agonist therapy who continue to experience persistent disease. Although the use of leukotriene receptor antagonists improves disease control in children and adults with asthma, the relationship between cysteinyl leukotriene levels and indices of daily asthma control has not been studied directly. In a study by Rabinovitch et al (p 635), 50 children, primarily with moderate-to-severe asthma, were followed by monitoring levels of urinary leukotriene E4 (LTE4), forced expiratory volume in 1 second (FEV1), and albuterol use. Levels of urinary LTE4 were directly associated with clinically significant declines in lung function and increased albuterol usage despite use of inhaled corticosteroids together with long-acting bronchodilators. This association was highest in children with persistent airway obstruction and was significantly blunted in children taking the cysteinyl leukotriene receptor 1 antagonist, montelukast. These data suggest that therapies designed to interfere with the activity of the cysteinyl leukotriene pathway may benefit children receiving inhaled corticosteroids and long-acting β-agonist therapy who continue to experience persistent disease. Cat and dust mite allergen levels in European homes Does CD14C-159T modulate the effect of farm exposure on allergy?A higher exposure to bacterial compounds—in particular, endotoxin—is purported to explain the lower prevalence of allergy in farm children. If early exposure to endotoxin may have a protective role, one might expect that genetic factors that modify endotoxin responsiveness would also influence the susceptibility to develop atopic diseases. In this issue of the Journal, Leynaert et al (p 658) investigate whether the effect of farm exposure on atopy is modulated by a CD14 promoter functional polymorphism. They analyzed data from 600 randomly selected young adults recruited in 2 French centers participating in the European Community Respiratory Health Survey. The results were consistent in the 2 centers. A lower risk of allergic rhinitis and atopy was observed in carriers of the CD14-159TT genotype as compared to -159CC subjects. Farm exposure in early life was also associated with a lower risk of nasal allergies and atopic sensitization in adulthood. However, the protective effect of farm exposure was slightly more marked in carriers of the -159TT genotype (adjusted odds ratio 0.42, and 0.24, respectively) than in -159CC+CT subjects. These findings are consistent with a gene-environment interaction whereby the CD14 C-159T would modulate the effect of environmental exposure on the development of atopy. A higher exposure to bacterial compounds—in particular, endotoxin—is purported to explain the lower prevalence of allergy in farm children. If early exposure to endotoxin may have a protective role, one might expect that genetic factors that modify endotoxin responsiveness would also influence the susceptibility to develop atopic diseases. In this issue of the Journal, Leynaert et al (p 658) investigate whether the effect of farm exposure on atopy is modulated by a CD14 promoter functional polymorphism. They analyzed data from 600 randomly selected young adults recruited in 2 French centers participating in the European Community Respiratory Health Survey. The results were consistent in the 2 centers. A lower risk of allergic rhinitis and atopy was observed in carriers of the CD14-159TT genotype as compared to -159CC subjects. Farm exposure in early life was also associated with a lower risk of nasal allergies and atopic sensitization in adulthood. However, the protective effect of farm exposure was slightly more marked in carriers of the -159TT genotype (adjusted odds ratio 0.42, and 0.24, respectively) than in -159CC+CT subjects. These findings are consistent with a gene-environment interaction whereby the CD14 C-159T would modulate the effect of environmental exposure on the development of atopy. Cat keeping, allergy, and asthmaThe relationship between pet exposure in childhood and the development of allergy and asthma continues to be unclear. It is plausible that exposure to pet allergens or microbial exposures associated with pet keeping is protective or, on the other hand, that there is selective avoidance of pets by subjects at risk for developing allergy and asthma. In this issue of the Journal, Svanes and coauthors (p 691) address this subject using data from 9812 subjects who participated in the European Community Respiratory Health Survey (ECRHS). Data were obtained when the subjects were 20-44 years of age (ECRHS I) and again an average of 9 years later (ECRHS II). Information on childhood asthma and pet keeping was retrospectively obtained at the first visit. Onset of asthma before age 5 years was associated with less cat keeping at 5-15 years (odds ratio [OR] = 0.60), an effect observed only when the parents did not have asthma or allergies. The onset of asthma up to age 15 years had no effect on subjects' pet keeping at the time of ECRHS I. Those with asthma and allergy, atopy, or cat-specific IgE at ECRHS I were less likely to have acquired a cat at follow-up (ECRHS II) but were no less likely to have retained one at ECRHS I. The authors conclude that selective avoidance subsequent to asthma or allergy was observed for childhood cat keeping and adult cat acquisition. Avoidance would produce an apparent “protective” effect of cats on childhood asthma. Avoidance was generally not observed for dogs or birds. The relationship between pet exposure in childhood and the development of allergy and asthma continues to be unclear. It is plausible that exposure to pet allergens or microbial exposures associated with pet keeping is protective or, on the other hand, that there is selective avoidance of pets by subjects at risk for developing allergy and asthma. In this issue of the Journal, Svanes and coauthors (p 691) address this subject using data from 9812 subjects who participated in the European Community Respiratory Health Survey (ECRHS). Data were obtained when the subjects were 20-44 years of age (ECRHS I) and again an average of 9 years later (ECRHS II). Information on childhood asthma and pet keeping was retrospectively obtained at the first visit. Onset of asthma before age 5 years was associated with less cat keeping at 5-15 years (odds ratio [OR] = 0.60), an effect observed only when the parents did not have asthma or allergies. The onset of asthma up to age 15 years had no effect on subjects' pet keeping at the time of ECRHS I. Those with asthma and allergy, atopy, or cat-specific IgE at ECRHS I were less likely to have acquired a cat at follow-up (ECRHS II) but were no less likely to have retained one at ECRHS I. The authors conclude that selective avoidance subsequent to asthma or allergy was observed for childhood cat keeping and adult cat acquisition. Avoidance would produce an apparent “protective” effect of cats on childhood asthma. Avoidance was generally not observed for dogs or birds.