Michael M Cyr

Fish Oil Supplementation in Pregnancy Modifies Neonatal Progenitors at Birth in Infants at Risk of Atopy

Dietary n-3 polyunsaturated fatty acids (PUFA) may represent a mode of allergy prevention. Cord blood (CB) CD34+ hemopoietic progenitors are altered in infants at risk of atopy. We therefore studied the effects of dietary n-3 PUFA supplementation during pregnancy on numbers and function of progenitors in neonates at high risk of atopy. In a double-blind study, atopic, pregnant women were randomized to receive fish oil capsules or placebo from 20 wk gestation until delivery. At birth, CB CD34+ cells were isolated and analyzed by flow cytometry for expression of cytokine (IL-5Rα, IL-3Rα, granulocyte/macrophage colony-stimulating factor Rα) or chemokine (CXCR4 and CCR3) receptors. CB cells were also cultured in methylcellulose assays for eosinophil/basophil colony-forming cells. At age 1 y, infants were clinically assessed for atopic symptoms and skin tests. Percentages of CB CD34+ cell numbers were higher after n-3 PUFA than placebo. Co-expression of cytokine or chemokine receptors on CD34 cells was not altered by n-3 PUFA supplementation. However, there were significantly more IL-5-responsive CB eosinophil/basophil colony forming units (Eo/B-CFU) in the fish oil, compared with the control, group. Overall, there was a positive association between CD34+ cells and IL-5-responsive Eo/B-CFU in CB and 1 y clinical outcomes, including atopic dermatitis and wheeze. Dietary n-3 PUFA supplementation during pregnancy in atopic mothers alters infant cord blood hemopoietic progenitor phenotype. This may have an impact on development of atopic disease.

Systemic aspects of allergic disease: the role of the bone marrow.

In recent years, there has been an increasing appreciation of the important contribution of bone-marrow-related, hemopoietic mechanisms to allergic diseases. Eosinophil/basophil-progenitor levels fluctuate in the peripheral blood during allergen exposure and the cells home to peripheral tissue, where they differentiate. It is becoming apparent that several cytokines, particularly IL-5, have multiple effects on progenitors and allergic inflammation. Within the past few years, studies of the therapeutic implications of this bone marrow contribution to atopy have been initiated; the effects of corticosteroids, leukotriene-receptor blockers, antagonism of IL-5 and modulation of differentiation by retinoic acid on progenitors will be reviewed.

Haemopoietic mechanisms in murine allergic upper and lower airway inflammation

Eosinophil recruitment to the airways, including involvement of haemopoietic eosinophil–basophil progenitors (Eo/B‐CFU), is primarily regulated by interleukin‐5 (IL‐5) and eotaxin. In this study, we investigated the haemopoietic mechanisms in upper and lower airway eosinophilic inflammation. Ovalbumin (OVA) sensitized and challenged BALB/c mice were used to establish isolated upper (UAC), isolated lower (LAC), or combined upper and lower airway (ULAC) inflammation. Airway, blood and bone marrow responses were evaluated in each model. Numbers of airway eosinophils and CD4+ cells were increased significantly in the nasal mucosa in UAC and ULAC mice, and in the lung tissue in LAC and ULAC groups. Levels of IL‐5 and eotaxin were increased significantly in the nasal lavage fluid (NL) in UAC and ULAC mice, and in the bronchoalveolar lavage fluid (BAL) in LAC and ULAC groups. The proportion of IL‐5‐responsive bone marrow Eo/B‐CFU was significantly higher than the control in all treatment groups, but peaked much earlier in the ULAC group. Kinetic studies revealed that IL‐5 and eotaxin in NL, BAL and serum peaked between 2 and 12 hr after OVA challenge in ULAC mice, and at 24 hr in UAC mice, related to the timing of maximal progenitor responses. These data support the concept that the systemic mechanisms linking rhinitis to asthma depend on the location and extent of airway allergen exposure.

Effects of a cysteinyl leukotriene receptor antagonist on eosinophil recruitment in experimental allergic rhinitis

The cysteinyl leukotrienes (cysLTs) are potent lipid mediators in allergic disease, acting through a receptor (cysLT1‐R) which can be targeted in rhinitis and asthma. We investigated the effects of cysLT1‐R antagonism in experimental allergic rhinitis, focusing on bone marrow eosinophil progenitor responses. BALB/c mice were sensitized, then given daily intranasal ovalbumin for 2 weeks, with montelukast sodium (5 mg/kg or 2·5 mg/kg) or placebo by gavage. Bone marrow eosinophil/basophil colonies were enumerated, and colony cells were morphologically assessed as indices of eosinophil differentiation and maturation. Montelukast treatment resulted in a significant decrease of eosinophils in the nasal mucosa, and in either bone marrow interleukin (IL)‐5‐, but not IL‐3‐, or granulocyte‐macrophage colony‐stimulating factor‐responsive eosinophil/basophil colony‐forming units, and IL‐5‐stimulated eosinophil maturation. These results indicate that cysLT1‐R antagonism in vivo limits both IL‐5‐responsive eosinophilopoiesis, acting at several stages of eosinophil differentiation and maturation. The anti‐allergic effects of cysLT1‐R antagonists are consistent with the concept that cysLTs and IL‐5 act together in the recruitment of eosinophils and eosinophil progenitors from the marrow during upper airway allergic inflammation.

Anti-allergic therapies: effects on eosinophil progenitors

Marked eosinophilic infiltration is the typical inflammatory response associated with allergic inflammation. Previous research involving animal and human models has established a role for the eosinophil/basophil hematopoietic progenitor in a systemic process of allergic inflammation. In this article, we will review the evidence implicating eosinophil/basophil progenitors in this systemic response and will discuss the rationale for targeting this cell in the treatment of allergic disease. In this context, we discuss corticosteroid treatment of allergic diseases, such as asthma and its effects on hematopoietic mechanisms, the effects of therapies that inhibit the actions of cysteinyl leukotrienes, the effects of in vivo blockade of the eosinophil-active cytokine interleukin-5, and the effects of antihistamines on hematopoiesis. It is suggested that several anti-allergic therapies exert their beneficial effects on allergic inflammation by influencing eosinophil production systemically. Therefore, targeting the systemic hematopoietic response may provide additional, more beneficial, therapeutic effects.

Associations between bacterial communities of house dust and infant gut

The human gut is host to a diverse and abundant community of bacteria that influence health and disease susceptibility. This community develops in infancy, and its composition is strongly influenced by environmental factors, notably perinatal anthropogenic exposures such as delivery mode (Cesarean vs. vaginal) and feeding method (breast vs. formula); however, the built environment as a possible source of exposure has not been considered. Here we report on a preliminary investigation of the associations between bacteria in house dust and the nascent fecal microbiota from 20 subjects from the Canadian Healthy Infant Longitudinal Development (CHILD) Study using high-throughput sequence analysis of portions of the 16S rRNA gene. Despite significant differences between the dust and fecal microbiota revealed by Nonmetric Multidimensional Scaling (NMDS) analysis, permutation analysis confirmed that 14 bacterial OTUs representing the classes Actinobacteria (3), Bacilli (3), Clostridia (6) and Gammaproteobacteria (2) co-occurred at a significantly higher frequency in matched dust-stool pairs than in randomly permuted pairs, indicating an association between these dust and stool communities. These associations could indicate a role for the indoor environment in shaping the nascent gut microbiota, but future studies will be needed to confirm that our findings do not solely reflect a reverse pathway. Although pet ownership was strongly associated with the presence of certain genera in the dust for dogs (Agrococcus, Carnobacterium, Exiguobacterium, Herbaspirillum, Leifsonia and Neisseria) and cats (Escherichia), no clear patterns were observed in the NMDS-resolved stool community profiles as a function of pet ownership.

The Effect of Desloratadine on Eosinophil/Basophil Progenitors and Other Inflammatory Markers in Seasonal Allergic Rhinitis: A Placebo-Controlled Randomized Study

Background: Eosinophil/basophil (Eo/B) progenitors fluctuate in the peripheral circulation during seasonal allergen exposure in atopic subjects. Several drugs have been shown to modulate Eo/B progenitor levels in the peripheral blood but, to date, the possible effect of antihistamines on Eo/B progenitors has not been explored. Our objective was to evaluate whether the antihistamine desloratadine (DL) can modulate peripheral blood Eo/B progenitors or other markers of allergic inflammation. Methods: We performed a randomized double-blind placebo-controlled study on the effects of DL on peripheral blood Eo/B progenitors in subjects with symptomatic, seasonal allergic rhinitis during a ragweed pollen season. Forty-five subjects were randomized to treatment for 4 weeks with DL 20 mg daily or placebo. Results: The expected fall in the number of Eo/B progenitors from baseline to 2 weeks of treatment was seen in the placebo group [median drop of 1.0 colony-forming unit (CFU)/106 cells], and was greater than in the DL group (median drop of 0.0 CFU/106 cells) (p = 0.013). The change in histamine concentration per colony from baseline to 2 weeks of treatment was lower in the DL group (median decrease of 6.1 pg/colony) compared to placebo (median increase of 1.8 pg/colony) (p = 0.01). An increase in the nasal lavage eotaxin concentration from baseline to 4 weeks of treatment was statistically significant in the placebo group but not in the DL group. Eo/B CFU were not affected by varyingin vitro concentrations of DL. Conclusion: These results suggest that DL can modulate aspects of allergic inflammation in vivo through mechanisms other than simple blockade of H1 histamine receptors.

Cord blood hemopoietic progenitor profiles predict acute respiratory symptoms in infancy

Atopy is characterized by eosinophilic inflammation associated with recruitment of eosinophil/basophil (Eo/B) progenitors. We have previously shown that Eo/B progenitor phenotypes are altered in cord blood (CB) in infants at high risk of atopy/asthma, and respond to maternal dietary intervention during pregnancy. As respiratory tract viral infections have been shown to induce wheeze in infancy, we investigated the relationship between CB progenitor function and phenotype and acute respiratory illness (ARI), specifically wheeze and fever. CB from 39 high‐risk infants was studied by flow cytometry for CD34+ progenitor phenotype and by ex vivo Eo/B‐colony forming unit (CFU) responses to cytokine stimulation in relation to ARI in the first year of life. A consistent relationship was observed between increased numbers of granulocyte/macrophage (GM)‐colony‐stimulating factor (CSF)‐ and IL‐3‐responsive Eo/B‐CFU in CB and the frequency/characteristics of ARI during infancy. Comparable associations were found between ARI and CB IL‐3R+ and GM‐CSFR+CD34+ cell numbers. Conversely, a reciprocal decrease in the proportion of CB IL‐5R+ cells was found in relation to the clinical outcomes. The elevation of IL‐3/GM‐CSF‐responsive Eo/B progenitors in high‐risk infants in relation to ARI outcomes suggests a mechanism for the increased severity of inflammatory responses in these subjects following viral infection.

Toll-like receptor-mediated eosinophil-basophil differentiation: autocrine signalling by granulocyte-macrophage colony-stimulating factor in cord blood haematopoietic progenitors.

Eosinophils are multi‐functional leucocytes that play a role in inflammatory processes including allergy and infection. Although bone marrow (BM) inflammatory cells are the main source of eosinophil‐basophil (Eo/B) differentiation‐inducing cytokines, a recent role has been demonstrated for cytokine induction through Toll‐like receptor (TLR)‐mediated signalling in BM progenitors. Having previously demonstrated that cord blood (CB) progenitors induce Eo/B colony‐forming units (CFU) after lipopolysaccharide (LPS) stimulation, we sought to investigate the intracellular mechanisms by which LPS induces Eo/B differentiation. Freshly isolated CD34‐enriched human CB cells were stimulated with LPS (and/or pharmacological inhibitors) and assessed for alterations in haematopoietic cytokine receptor expression and signalling pathways by flow cytometry, Eo/B CFU in methylcellulose cultures, and cytokine secretion using Luminex assays. The LPS stimulation resulted in a significant increase in granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐responsive, as opposed to interleukin‐5‐responsive, Eo/B CFU, which also correlated with significant increases in CD34+ cell GM‐CSFRα expression. Functionally, CB CD34+ cells secrete abundant amounts of GM‐CSF following LPS stimulation, via a p38 mitogen‐activated protein kinase (MAPK)‐dependent mechanism; this secretion was responsible for Eo/B CFU formation ex vivo, as shown by antibody blockade. We show for the first time that LPS stimulation of CB progenitor cells results in autocrine activation of p38 MAPK‐dependent GM‐CSF secretion facilitating Eo/B differentiation ex vivo. This work provides evidence that early life exposure to products of bacterial agents can modulate Eo/B differentiation, representing a novel mechanism by which progenitor cells can respond to microbial stimuli and so affect immune and inflammatory responses.

The effect of desloratadine on eosinophil/basophil progenitors and other inflammatory markers in seasonal allergic rhinitis: A placebo-controlled randomized study

BACKGROUND Eosinophil/basophil (Eo/B) progenitors fluctuate in the peripheral circulation during seasonal allergen exposure in atopic subjects. Several drugs have been shown to modulate Eo/B progenitor levels in the peripheral blood but, to date, the possible effect of antihistamines on Eo/B progenitors has not been explored. Our objective was to evaluate whether the antihistamine desloratadine (DL) can modulate peripheral blood Eo/B progenitors or other markers of allergic inflammation. METHODS We performed a randomized double-blind placebo-controlled study on the effects of DL on peripheral blood Eo/B progenitors in subjects with symptomatic, seasonal allergic rhinitis during a ragweed pollen season. Forty-five subjects were randomized to treatment for 4 weeks with DL 20 mg daily or placebo. RESULTS The expected fall in the number of Eo/B progenitors from baseline to 2 weeks of treatment was seen in the placebo group [median drop of 1.0 colony-forming unit (CFU)/10(6) cells], and was greater than in the DL group (median drop of 0.0 CFU/10(6) cells) (p = 0.013). The change in histamine concentration per colony from baseline to 2 weeks of treatment was lower in the DL group (median decrease of 6.1 pg/colony) compared to placebo (median increase of 1.8 pg/colony) (p = 0.01). An increase in the nasal lavage eotaxin concentration from baseline to 4 weeks of treatment was statistically significant in the placebo group but not in the DL group. Eo/B CFU were not affected by varying in vitro concentrations of DL. CONCLUSION These results suggest that DL can modulate aspects of allergic inflammation in vivo through mechanisms other than simple blockade of H1 histamine receptors.