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P G Holt

Publications and source records attributed to P G Holt.

At least 19 recordsLinked to original sources
PubMed2006

Cytokine responses to allergens during the first 2 years of life in Estonian and Swedish children.

BACKGROUND: The prevalence of atopic disease among children in the formerly socialist countries in Europe, with a life style similar to that prevailing in Western Europe 30-40 years ago, is low, whereas there has been a pronounced increase in industrialized countries over the last decades. The environment during infancy influences the risk of developing allergy for many years, perhaps even for life. OBJECTIVE: To investigate the development of allergen-specific cytokine responses during the first 2 years of life in two geographically adjacent countries with marked differences in living conditions and incidence of atopic diseases, i.e. Estonia and Sweden. METHODS: The development of immune responses to food (beta-lactoglobulin (BLG) and ovalbumin (OVA)) and inhalant (cat and birch) allergens was studied from birth up to the age of 2 years in 30 Estonian and 76 Swedish infants. Clinical investigation and skin prick tests were performed and blood samples were obtained at birth and at 3, 6, 12 and 24 months. RESULTS: The levels of IL-5, IL-10 and IL-13 secreted by peripheral blood mononuclear cells stimulated with BLG, OVA and cat allergen in Estonian and Swedish infants declined during the first 3 months of life. All cytokines then progressively increased in the Swedish infants, indicating the replacement of non-specifically responding immature cord blood T cells with specific T memory cells, which are primed postnatally. The resurgence of allergen-specific responses in the Estonian infants was less marked. These differences were particularly notable for birch-specific T cell responses, which correlated with development of atopic disease in the Swedish children. CONCLUSIONS: The development of specific T cell memory to food and inhalant allergens during the first 2 years of life differs between infants living in Sweden and Estonia, and mirrors the disparate patterns of expression of allergic disease which subsequently develops in the respective populations.

Allergens↗
PubMed2005

Sensitization to airborne environmental allergens: unresolved issues.

Despite considerable advances in identifying the environmental agents that trigger allergy and the immunological mechanisms involved, progress in developing effective treatments remains frustratingly slow. Is it time to rethink some of the paradigms guiding this research?

Air Pollutants↗
PubMed2004

Staphylococcal enterotoxin-B-mediated stimulation of interleukin-13 production as a potential aetiologic factor in eczema in infants.

BACKGROUND: Staphylococcus aureus colonization has been found in 80-100% of lesional skin from patients with atopic eczema dermatitis syndrome (AEDS) and is thought to have a role in the pathogenesis of the disease. Furthermore, up to 65% of S. aureus from lesional skin has been shown to produce toxigenic superantigens. METHODS: Using a cohort of 11 children under 2 years of age diagnosed with AEDS, we isolated peripheral blood mononuclear cells, cultured them with staphylococcal enterotoxin B (SEB) and phytohaemagglutinin, and assessed the cytokine response profiles. Plasma was also collected for immunoglobulin E analysis. In addition, skin and nasal swabs were taken and cultured to determine the presence of SEB-producing S. aureus by polymerase chain reaction (PCR) and reverse passive latex agglutination. RESULTS: We found a significant increase in the production of the SEB-induced cytokines interleukin (IL)-5 and IL-13 in the patient group when compared with non-atopic, healthy controls. For IL-13, there was almost no overlap in the levels between the groups. However, there was no correlation between SEB-induced IL-13 and disease severity. This difference was not seen when heat-inactivated S. aureus was used to stimulate the cells. CONCLUSIONS: IL-13 is an important factor in AEDS development in early childhood, and prophylactic anti-staphylococcal treatment may provide protection from AEDS in atopic individuals.

Antigens, Bacterial↗
PubMed2004

Enhancement of vaccine-specific cellular immunity in infants by passively acquired maternal antibody.

The known protective effects of passively acquired maternal antibody on the resistance of newborns to infections have prompted widespread interest in maternal vaccination. However, a range of animal model and human studies indicate potential inhibitory effects of maternal antibody on vaccine-specific humoral responses in infants. In the present study we have examined the relationship between maternally acquired TT-specific IgG present before DTaP vaccination and subsequent TT-specific T-cell memory responses at 12 and 18 months, in a cohort of 118 infants. We demonstrate a strong positive association between TT-specific cellular immunity as evidenced by increased IL-4, IL-5 and IL-13 responses, and maternal TT-specific IgG.

Antibodies, Bacterial↗
PubMed2004

Effects of n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition.

OBJECTIVE: The aim of this study was to assess the effects of fish oil supplementation in pregnancy on maternal erythrocyte fatty acid composition at different stages of pregnancy and in the post-partum period, and on neonatal erythrocyte fatty acid composition. DESIGN: A double-blind, randomised, placebo-controlled study. SETTING: : Subiaco, Western Australia. SUBJECTS: In all, 98 women booked for delivery at St John of God Hospital, Subiaco, were recruited from private rooms of obstetricians. In total, 83 women and their healthy full-term babies completed the study. INTERVENTION: Women received either 4 g of fish oil (n=52) (56% docosahexaenoic acid (DHA) and 28% eicosapentaenoic acid (EPA) or placebo (olive oil) (n=46) per day from 20 weeks gestation until delivery. MAIN OUTCOME MEASURES: Erythrocyte phospholipid fatty acids were measured in maternal peripheral blood at 20, 30 and 37 weeks of pregnancy and at 6 weeks post partum, and from cord blood collected at birth. RESULTS: Compared to the control group, maternal EPA and DHA were significantly higher in the fish oil group at 30 and 37 weeks gestation, and remained elevated at 6 weeks post partum (P<0.001). The proportions of n-6 polyunsaturated (arachidonic acid, 22:3n-6 and 22:4n-6) were significantly lower in the fish oil supplemented group at the same time periods (P<0.001). Similarly, the proportions of EPA and DHA were significantly higher (P<0.001), and those of n-6 polyunsaturated fatty acids arachidonic acid, 20:3n-6, 22:3n-6 and 22:4n-6 were significantly lower (P<0.001), in erythrocytes from neonates in the fish oil group, compared to those in the control group. CONCLUSION: Fish oil supplementation from 20 weeks of pregnancy until birth is an effective means of enhancing n-3 fatty acid status of both mothers and neonates. Furthermore, the changes in maternal erythrocyte fatty acid composition are retained until at least 6 weeks post partum. It is essential to assess the effects of concomitant decreases in arachidonic acid status before any dietary recommendations can be made. SPONSORSHIP: The study was supported by grants from the NH & MRC and Raine Medical Research Foundation, Australia.

Adult↗
PubMed2003

Association between antenatal cytokine production and the development of atopy and asthma at age 6 years.

BACKGROUND: Various lines of evidence suggest that antenatal factors are important in determining susceptibility to atopy and asthma. One possible mechanism is cytokines, production of which in the placenta is high throughout gestation and which protect placental integrity via control of local immunological homoeostasis. We investigated antenatal cytokine concentrations in a prospective birth cohort, intensively monitored for atopy and asthma outcomes at age 6 years. METHODS: Cryopreserved cord-blood serum samples from 407 children were assayed for interleukins 4, 5, 6, 10, 12, and 13, interferon gamma, and tumour necrosis factor alpha (TNFalpha). Associations between family, antenatal, and perinatal factors, cord-blood cytokine concentrations, and atopy or asthma outcomes were analysed by logistic regression. Causal effects of cytokines on outcomes were estimated by propensity scores based on family, antenatal, and perinatal factors. FINDINGS: Detectable cord-blood concentrations of interleukin 4 and interferon gamma were each associated with lower risk of physician-diagnosed asthma (adjusted odds ratios 0.60 [95% CI 0.37-0.99] and 0.60 [0.37-0.97] respectively), current asthma (0.59 [0.33-1.00] and 0.39 [0.22-0.71]), and current wheeze (0.55 [0.32-0.93] and 0.52 [0.31-0.90]) and atopy (sensitisation to some inhalant allergens) outcomes at 6 years. High concentrations of TNFalpha were associated with lower risk of atopy but not with asthma risk. These associations were broadly unaltered by propensity-score adjustment. Maternal smoking was associated with higher risk of both wheeze at 6 years and lower concentrations of interleukin 4 and interferon gamma in cord blood. INTERPRETATION: The mechanism underlying attenuated T-helper-1/T-helper-2 cytokine production in high-risk children also apparently operates in control of cytokine production in the fetoplacental unit. The finding that this mechanism is dysregulated by maternal smoking suggests it is a target for antenatal environmental factors relevant to asthma aetiology.

Asthma↗
PubMed2003

Developmental factors associated with risk for atopic disease: implications for vaccine strategies in early childhood.

There is growing interest in the potential interactions between infant vaccination and risk for development of atopic disease. The aspect of this issue which has dominated this debate concerns suggestions that infant vaccination may stimulate allergic sensitisation. These suggestions derive from retrospective epidemiological analyses and will remain speculative unless they can be confirmed in prospective studies, particularly as conflicting findings have been reported. However, there is a potentially more important issue surfacing in this debate, which entails the converse situation, i.e. that genetic risk for atopy influences capacity to respond to vaccination during infancy. Support for the latter possibility comes from recent studies on the role of developmental factors which determine immune competence during infancy, and attendant risk for inflammatory and infectious diseases. The relevant findings are reviewed briefly below.

Environment↗
PubMed2003

The value of perinatal immune responses in predicting allergic disease at 6 years of age.

BACKGROUND: Characterizing early abnormalities in immune development of allergic individuals provides an important basis for defining disease pathogenesis and future prevention strategies. This study compares patterns of early immune responses in an established cohort based on allergic outcomes and allergen skin prick test (SPT) reactions at 6 years of age. METHODS: Children from an original birth cohort (n = 60) consisting of 44 high risk (HR) (family history of allergy) and 16 low risk (LR) (no family history) were reassessed at 6 years of age. Detailed clinical information about allergic disease was obtained (n = 53) and a subgroup (n = 31) consented to have allergen SPT to common food and inhalant allergens. Data from previous immunological assessments performed at birth, 1 and 2 years of age, including lymphoproliferation and cytokine [interleukin (IL)-4, IL-5, IL-6, IL-10, IL-13 and interferon (IFN)-gamma] responses to ovalbumin (OVA), house dust mite (HDM), cat allergen (Fel d 1), phytohaemaglutinin (PHA) and tetanus toxoid, were re-analysed based on the 6-year clinical outcomes. RESULTS: Twenty-eight HR and three LR children had a clinical history of allergic disease at 6 years of age including doctor diagnosed asthma (n = 17) and/or eczema (n = 24). Most children (78%) with atopy at 6 years had positive SPT to the allergens tested, and 70% had symptoms within the last year. Children at genetic risk (family history) of allergy had weaker (P = 0.017) polyclonal T helper 1 (Th1) IFN-gamma responses in the neonatal period compared with LR children. Although children with allergic disease at 6 years also tended to have weaker neonatal IFN-gamma responses compared to those with no symptoms, but this was not quite significant (P = 0.05). A positive SPT to HDM at 6 years was associated with higher IL-13 responses to HDM at 1 year (P = 0.02), whereas allergic disease at 6 years was associated with higher IL-5 messenger RNA (mRNA) responses to HDM at 1 year (P = 0.01). Despite these associations, regression analysis demonstrated that the only significant early predictors of allergic sensitization at 6 years of age were a family history of allergic disease, and atopic symptoms at 2 years. Importantly, none of the early immunological parameters measured were significantly predictive of allergic disease or allergic sensitization in these 6-year-olds. CONCLUSIONS: Although our observations suggest that subtle differential alterations in cytokine responses during early immune development are associated with different aspects of subsequent atopy, there are still no early predictive biomarkers of disease. A positive family history of allergy remains the dominant predictive factor.

Allergens↗
PubMed2003

Maternal smoking in pregnancy alters neonatal cytokine responses.

BACKGROUND: Maternal cigarette smoking in pregnancy is an important, common and avoidable exposure that has been linked with elevated cord blood (CB) immunoglobulin E levels and subsequent asthma and allergic disease in childhood. Despite this, there is still very little information about the immunological effects of maternal smoking on the fetus. METHODS: This aim of this study was to compare cord blood mononuclear cell (CBMC) cytokine responses to allergens [ovalbumin (OVA) or house dust mite (HDM)] and mitogens [concanavalin A (ConA) or phytohemaglutinen (PHA)] in neonates whose mothers smoked throughout pregnancy (n = 17) with responses of neonates whose mothers never smoked (n = 40). Cell cultures were stimulated for 24 h and supernatants collected for cytokine detection by enzyme-linked immunosorbent assay [interleukin (IL)-13, IL-6, interferon (IFN)gamma and IL-10]. Cell pellets were also collected for cytokine mRNA detection (IL-5, IL-9, IFNgamma). RESULTS: Maternal smoking in pregnancy was associated with significantly higher neonatal T helper type 2 (IL-13 protein) responses to both HDM (P = 0.01) and OVA (P = 0.035). These effects remained statistically significant after allowing for confounding factors, including the effects of maternal atopy. Similar trends were also seen for IL-9mRNA, IL-5mRNA and IL-6 responses, although these were not statistically significant. Although IFNgamma mRNA responses to PHA (P = 0.015) and ConA (P = 0.025) were lower if mothers smoked in pregnancy, there were no differences in neonatal (Th1) IFNgamma protein responses to allergens or mitogens. CONCLUSIONS: These findings indicate that maternal cigarette smoking can modify aspects of fetal immune function and highlight the need for further studies in this area.

Adult↗
PubMed2003

Maternal fish oil supplementation in pregnancy reduces interleukin-13 levels in cord blood of infants at high risk of atopy.

BACKGROUND AND OBJECTIVES: The epidemiological association between higher dietary n-3 polyunsaturated fatty acids (PUFA) and lower prevalence of asthma, has led to interest in the role of early dietary modification in allergic disease prevention. In this study we examined the effects of maternal n-3 (PUFA)-rich fish oil supplementation on cord blood (CB) IgE and cytokine levels in neonates at risk of developing allergic disease. METHODS: In a randomized double-blind, placebo-controlled trial, 83 atopic pregnant women received either fish oil capsules (n = 40) containing 3.7 g n-3 PUFA/day or placebo capsules (n = 43) from 20 weeks gestation until delivery. CB cytokine levels (IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, TNF-alpha and IFN-gamma) and total IgE levels were measured and compared between the two groups. Fatty acid composition of red cell membranes was analysed by gas chromatography and the relationships among PUFA, cytokine and IgE levels were examined. RESULTS: Maternal fish oil supplementation resulted in a significant increase in n-3 PUFA levels (P < 0.001) in neonatal erythrocyte membranes. Neonates whose mothers had fish oil supplementation had significantly lower plasma IL-13 (P < 0.05) compared to the control group. There was also a significant inverse relationship between levels of n-3 PUFA in neonatal cell membranes and plasma IL-13. There was no difference in levels of IgE and the other cytokines measured. CONCLUSIONS: This study provides preliminary evidence that increasing neonatal n-3 PUFA levels with maternal dietary supplementation can achieve subtle modification of neonatal cytokine levels. Further assessment of immune function and clinical follow-up of these infants will help determine if there are any significant effects on postnatal immune development and expression of allergic disease.

Double-Blind Method↗
PubMed2003

Specific patterns of responsiveness to microbial antigens staphylococcal enterotoxin B and purified protein derivative by cord blood mononuclear cells are predictive of risk for development of atopic dermatitis.

BACKGROUND: Mononuclear cells from children with active atopic dermatitis (AD) have been reported to be hyper-responsive to certain microbial stimuli, in particular staphylococcal enterotoxin B (SEB). However, it is not known whether this responsiveness is acquired during disease development, or is inherent. We investigated this question in a cohort of children at high risk of atopy followed prospectively from birth to age 3 years. We asked whether their cord blood mononuclear cell (CBMC) cytokine responses to SEB, to an unrelated microbial stimulus purified protein derivative (PPD), or to common allergens, were predictive of risk for subsequent AD development during infancy. METHODS: Children at high risk of developing atopy were randomly selected from an ongoing prospective cohort. Cord blood was collected at birth. The children were seen at 6 months, 1, 2 and 3 years and examined for the development of AD. IFN-gamma, IL-5, IL-10 and IL-13 production by CBMC cultured in the presence of SEB, PPD, PHA, house dust mite (HDM) allergen, ovalbumin (OVA) and cat allergen was determined. RESULTS: SEB-induced IL-5 production by CBMC was elevated in children who developed AD at 6 months (P = 0.01) and 2 years (P = 0.009). PPD-induced IL-5 responses were also elevated in CBMC from children who developed AD at 6 months, 2 years and 3 years (P = 0.05, P = 0.06 and P = 0.06, respectively), as were PPD-induced IL-10 responses (P = 0.05 at 1 years, P = 0.007 at 2 years, P = 0.003 at 3 years) and corresponding IFN-gamma responses (P = 0.05 at 6 months, P = 0.003 at 2 years, P = 0.0004 at 3 years). Increased IL-10 responses to HDM allergen were also observed throughout the observation period in CBMC from children who developed AD. CONCLUSION: Children who develop infantile AD appear to have a predisposition to respond to SEB in a Th2-dominant manner involving selective stimulation of IL-5 production. The increased IL-10 and IFN-gamma induced in response to PPD by children with AD may point to additional intrinsic differences in responses to microbial stimuli between those at high vs. those at low risk for AD, which merit more detailed investigations.

Cells, Cultured↗
PubMed2003

Neonatal interleukin-12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods.

BACKGROUND AND OBJECTIVES: A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. In this study we examined the relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years. METHODS: The capacity of circulating neonatal (and maternal) APC to produce IL-12 p70 in response to LPS (and IFN-gamma) stimulation was assessed in a group of 60 children with previously well-characterized immune responses to allergens and atopic outcomes. The IL-12 responses were compared with allergen-induced lymphoproliferation (to house dust mite (HDM) ovalbumin (OVA), cat and beta-lactoglobulin (BLG)) and IL-13 and IFN-gamma cytokine responses (to OVA, HDM and phytohaemaglutinin (PHA)) in the neonatal and postnatal periods. IL-12 responses were also compared according to atopic risk and atopic outcomes (doctor-diagnosed asthma, eczema, food allergies and sensitization as evidenced by skin prick testing) at 6 years clinical follow-up. RESULTS: Maternal peripheral blood mononuclear cells (PBMC) synthesized significantly greater amounts of IL-12 than neonatal PBMC, though within maternal-infant pairs IL-12 responses were significantly correlated (r = 0.4, P = 0.019). Moreover, neonatal IL-12 responses were positively correlated with neonatal allergen proliferation for HDM (r = 0.6, P < 0.0001), OVA (r = 0.55, P < 0.0001), cat (r = 0.5, P = 0.003) and BLG (r = 0.55, P = 0.001), but negatively correlated with neonatal IL-13 responses to both allergens tested (HDM: r = - 0.4, P = 0.03 and OVA: r = - 0.5, P = 0.001). Both neonatal and maternal IL-12 responses were positively correlated with postnatal IFN-gamma responses to HDM at 12, 18 and 24 months of age (responses after age of 2 years were not assessed). There was no relationship between atopic risk and IL-12 capacity in the neonatal period, but there was a (non-significant) trend for neonatal IL-12 responses to be lower in the high-risk children who developed clinical allergy at 6 years (compared with the low risk group) although the number in this analysis was small. CONCLUSIONS: Reduced APC IL-12 production in the perinatal period was associated with reduced T cell activation (lymphoproliferation), stronger neonatal Th2 responses, and weaker Th1 responses to allergen in the postnatal period. This supports the notion that variations in APC function in early life may contribute to altered allergen-specific cytokine responses associated with later allergy.

Allergens↗
PubMed2003

Breast feeding and respiratory morbidity in infancy: a birth cohort study.

AIM: To examine the relation between the duration of breast feeding and morbidity as a result of respiratory illness and infection in the first year of life. METHODS: Prospective birth cohort study of 2602 live born children ascertained through antenatal clinics at the major tertiary obstetric hospital in Perth, Western Australia. Main outcome measures were hospital, doctor, or clinic visits, and hospital admissions for respiratory illness and infection in the first year of life. Main exposure measures were the duration of predominant breast feeding (defined as the age other milk was introduced) and partial (any) breast feeding (defined as the age breast feeding was stopped). Main confounders were gender, gestational age less than 37 weeks, smoking in pregnancy, older siblings, maternal education, and maternal age. RESULTS: Hospital, doctor, or clinic visits for four or more upper respiratory tract infections were significantly greater if predominant breast feeding was stopped before 2 months or partial breast feeding was stopped before 6 months. Predominant breast feeding for less than six months was associated with an increased risk for two or more hospital, doctor, or clinic visits and hospital admission for wheezing lower respiratory illness. Breast feeding for less than eight months was associated with a significantly increased risk for two or more hospital, doctor, or clinic visits or hospital admissions because of wheezing lower respiratory illnesses. CONCLUSIONS: Predominant breast feeding for at least six months and partial breast feeding for up to one year may reduce the prevalence and subsequent morbidity of respiratory illness and infection in infancy.

Bottle Feeding↗
PubMed2002

Cellular immune responses to ovalbumin and house dust mite in egg-allergic children.

BACKGROUND: Although IgE-mediated food (egg) allergy is typically lost with age the underlying immune mechanisms are not understood, particularly in relation to the development of persistent IgE-mediated aeroallergen sensitivity. METHODS: Lymphoproliferation and cytokine responses (IL-5, IL-10, IL-13 and IFN-gamma) to house dust mite (HDM) allergen and egg ovalbumin (OVA) were assessed using peripheral blood mononuclear cells (PBMC) from children aged 6 months to 5 years (n = 59) with acute IgE-mediated egg allergy (urticaria and angiedema or anaphylaxis), as confirmed by positive skin prick testing (SPT). Of these 46 had positive SPT on the day of blood collection and 13 had outgrown egg allergy (negative SPT and successful egg challenge). Where possible, responses were compared with previous data from nonallergic children of similar ages (n = 107). RESULTS: Transient lymphoproliferative responses to OVA were seen in both egg-allergic and nonallergic children, but were more marked and more prolonged in egg-allergic children. Younger egg-allergic children (< 18 months) showed a mixed Th0 cytokine response to OVA, with readily detectable IFN-gamma, IL-5, IL-13 IL-10. Although IL-13 and IL-5 responses (OVA) correlated in younger egg-allergic children, there was a dissociation of these Th2 responses with age. Loss of clinical reactivity to egg was associated with almost complete loss of IL-5 responses and OVA-specific lymphoproliferation. Although IL-13 levels tended to be lower with age, this was not significant. Strong IFN-gamma and IL-10 responses to OVA persisted in older children after loss of OVA-specific lymphoproliferation. Lymphoproliferative responses to HDM also developed earlier in egg-allergic children compared with nonallergic children. Th1 (IFN-gamma) responses to HDM were largely below detection prior to 18 months of age, but increased significantly with age. In egg-allergic children Th2 (IL-5, IL-13) HDM responses also progressively increased with age. At 3 years of age almost all egg-allergic children had positive SPT to HDM and positive lymphoproliferative responses to HDM, with strong Th1 and Th2 (Th0) cytokine production. CONCLUSIONS: IL-5 responses (rather than IL-13) responses most closely reflected clinical food allergy, with dissociation of IL-5 and IL-13 responses in older and egg-tolerant children. In this population, food and aeroallergen sensitivity was not associated with inability to produce IFN-gamma, but rather with mixed Th2 and Th1 (Th0) responses. Strong IL-10 and IFN-gamma responses where associated with the development of tolerance, suggesting persistent 'regulatory' populations of OVA-specific T cells, rather than clonal deletion of OVA responsive T-cells.

Animals↗
PubMed2002

Reciprocal patterns of allergen-induced GATA-3 expression in peripheral blood mononuclear cells from atopics vs. non-atopics.

BACKGROUND: T helper (Th)2 cytokines are considered to play a central role in the induction and expression of allergic disease. However, the relative importance of individual cytokines is unclear, and overall disease pathogenesis appears to involve the coordinate activities of a range of Th2 cytokines acting in sequence or in parallel. The present study examines an alternative approach to the study of cytokine gene function in atopy, focusing instead upon T cell transcription factors (TFs) which play a role in the regulation of multiple cytokine genes. OBJECTIVE: To investigate the allergen-induced expression of the TF GATA-3 and c-Maf in peripheral blood mononuclear cells (PBMCs) and in cytokine-driven Th polarization. METHODS: PBMC from house dust mite (HDM)-atopic and non-atopics were stimulated in vitro with allergen or anti-CD3/IL-2. TF expression was analysed by semiquantitative RT-PCR and major findings were validated by real-time PCR. Cell separations were performed to analyse the contribution of CD45RO+ cells. CD4+ cord blood cells were Th1 or Th2 polarized in vitro by exogenous cytokines and TF expression analysed by Northern blot and real-time PCR. Results We demonstrate for the first time that during differentiation of CD4+ CD45RA+ naïve human T cells towards Th2 commitment, and during allergen-specific reactivation of peripheral CD4+ CD45RO+ Th2 memory cells in established atopics, expression of the Th2-associated TF GATA-3 is rapidly up-regulated, whereas T cells from non-atopics display equally rapid GATA-3 down-regulation under identical conditions of allergen stimulation. CONCLUSION: These findings identify Th2-associated TFs as key determinants of the atopic phenotype, suggesting their unique potential as therapeutic targets for disease control.

Adult↗
PubMed2002

The effects of respiratory infections, atopy, and breastfeeding on childhood asthma.

The objectives of the present study were to quantify the association of atopy and respiratory infections with asthma, and exclusive breastfeeding with respiratory illness, atopy and asthma in children. A cohort study of 2,602 children enrolled prior to birth and followed prospectively, provided data on respiratory illness, the method of feeding in the first year of life, as reported on a prospective diary card, and current asthma at the age of 6 yrs (defined as doctor-diagnosed asthma with wheeze in the last year or cough without a cold, and currently taking either preventer or reliever asthma medication), as reported by parental questionnaire. Atopy was defined by a positive skin-prick test assessed at the age of 6 yrs. Wheezing lower respiratory illness (LRI) in the first year of life, particularly multiple episodes of wheezing LRI, increased the risk for current asthma in both nonatopic (odds ratio (OR) 4.10, p< or =0.0005) and atopic children (OR 9.00, p< or =0.0005), but did not increase the risk for atopy. In contrast, up to three upper respiratory tract infections demonstrated a negative association and four or more a positive risk for current asthma in unadjusted (p=0.006) and adjusted (p=0.057) analysis. Following adjustment, exclusive breastfeeding for <4 months was associated with an increased risk for current asthma (OR 1.36, 95% confidence interval 1.00-1.85, p=0.047). Wheezing lower respiratory illness in the first year of life and atopy are independently associated with increased risk for current asthma at the age of 6 yrs, suggesting that their effects are mediated via different causal pathways and that these risk factors are multiplicative when they operate concomitantly within individual children. Exclusive breastfeeding protects against asthma via effects on both these pathways, as well as through other as yet undefined mechanisms.

Asthma↗