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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 γ, and tumour necrosis factor α (TNFα). 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 γ 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 TNFα 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 γ 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. [Copyright &y& Elsevier]

A microculture system was developed for in vitro IgE synthesis employing human peripheral blood leucocytes (PBL), comprising 1.0 × 106 cells in 1.0 ml serum-supplemented growth medium, in round-bottomed tubes. Examination of the kinetics of IgE synthesis indicated that production was relatively linear during culture for up to 12 days, and was not susceptible to stimulation with polyclonal B cell mitogen. Employing a standardized 7-day culture period, PBL IgE synthesis was compared within a group of 50 volunteers, comprising normal non-atopic individuals exhibiting serum IgE titres <50 units/ml, and moderate atopics with serum titres up to approximately 400 units/ml. PBL IgE synthesis was found to reflect closely the serum IgE status of the cell donor, a feature thus far unique to this culture system, and indicative of the preservation of normal in vivo regulatory mechanisms in the in vitro cultures. [ABSTRACT FROM AUTHOR]

The study below comprises prospective analysis of patterns of allergenspecific T-cell reactivity in a cohort of 23 children bled at'regular intervals from 6-10 weeks to 2 years of age, together with cross sectional studies on panels of cord and adult blood samples. The results indicate reciprocal patterns of responses to dietary and inhalant allergens, the former being frequent in infancy but rare in adults, whereas the latter are preserved and expand between infancy and adulthood. These findings are consistent with a recently proposed model for the development of immunity to environmental allergens which involves allergen-driven T-cell "selection" during early life leading to deletion of food allergen-specific T-cells via the induction of specific anergy, with concomitant selection and ultimately expansion of mutually exclusive TH- I-like or TH-2-like reactivity to inhalant allergens via Immune Deviation mechanisms. [ABSTRACT FROM AUTHOR]

The characteristics of the T-cell population in the healthy human lung have been investigated by analysing the properties of T-cell clones derived from bronchoalveolar lavage (BAL) samples and comparing them with T cells cloned from the blood of the same individuals. The proportions of CD4+ and CD8+ T cells in the starting populations from HAL and blood were similar although only 14% of BAL T cells were CD45RA+ compared to 70% of blood T cells. The precursor frequency of T-cell clones derived from BAL was less than from blood. The cytokine profiles [after phytohaemagglutinin (PHA) stimulation] of the clones derived from both sources were markedly different and these differences lay in the CD4+ population. BAL-derived CD4+ clones produced interferon-γ (IFN-γ) more frequently than did those from blood while blood-derived clones were more likely to produce interleukin-2 (IL-2) than those from BAL. IL-4 was produced by the majority of BAL- or blood-derived clones (93% and 88% respectively) either along with IFN-γ (BAL) or lL-2 (blood). The cytokine profiles of BAL-derived T-cell clones are consistent with those derived from lung interstitium and suggest that the BAL T-cell populations reflect those in the lung wall. Whether the unique properties of lung T cells are acquired after leaving the blood or whether there is selective entry of T-cell subpopulations into the lung remains to be determined. [ABSTRACT FROM AUTHOR]

The regulating effects of IL-4 and pokeweed mitogen on IgE synthesis in vitro by human peripheral blood leucocytes has been compared with the corresponding effect of these regulators on the expression of IgE mRNA. The latter was measured by dot blot hybridization with an oligonucleotide coding for a unique six amino acid region of the CHψ2 domain. Specificity of the oligonucleotide probe was established by its inability to hybridize with RNA extracted from HMY-2 (IgG) and XQ-15 (IgM) secreting cell lines whilst producing intense signals with RNA extracted from the lgE secreting cell line U266. Whilst IgE mRNA was detected in RNA extracted from PBL of both atopic and control subjects, spontaneous IgE synthesis was restricted to atopic PBL. IL-4 increased both IgE mRNA and IgE synthesis in all PBL samples but PWM, while significantly increasing IgE mRNA expression either failed to modify IgE synthesis or actively suppressed it. The assay system employed to quantitate IgE synthesis in vitro was shown to be inhibited by both IgE binding factors and IgG anti-IgE autoantibodies which are produced in PBL cultures. IgE mRNA levels might therefore more accurately monitor the regulatory effects of IL-4 and PWM on IgE synthesis than quantitation of the IgE by radioimmunoassay. [ABSTRACT FROM AUTHOR]

Repeated exposure of Brown Norway rats to an aerosol of ovalbumin (OVA) induced a state of antigen-specific immunological tolerance, particularly in the IgE isotype. Tolerance was transferable to naive syngeneic animals by inoculation of splenic T cells from tolerant rats. Sequential depletion of tolerant spleen cells by sorting techniques prior to adoptive transfer, employing T-cell subset-specific monoclonal antibodies, indicated that the cells mediating tolerance were CD3+, CD4 , CD5+ and CD8+, but lacked α or β chains in the T-cell receptor (TcR), suggesting that they may be part of the γ/δ T-cell lineage. Consistent with this suggestion, the sorted population demonstrated considerable enrichment for TcRγ chain-specific mRNA. As few as 2 × 103 cells are sufficient to adoptively transfer tolerance in 200-g adult rats in this model. [ABSTRACT FROM AUTHOR]

lgE and IgG synthesis was demonstrated in cultures of isolated B cells from normal subjects. and those manifesting mild to severe atopy. Titration of autochthonous T cells into B cell cultures revealed both IgE isotype-specific 1-help and 1-suppression at low and high T: B ratios respectively. Increasing levels of help for lgG synthesis usually accompanied the stepwise addition of the same T cells to autochthonous or allogeneic B cell cultures. Experiments comparing the activity of putative IgE suppressor T cells in autochthonous versus allogeneic H cell cultures indicated that allogeneic interactions per se selectively inhibit IgE B cells. This finding seriously questions earlier conclusions of a causal relationship between suppressor cell deficiency and the expression of the allergic phenotype. [ABSTRACT FROM AUTHOR]

Background There is increasing evidence that the T-cell reactivity to environmental allergens underlying expression of allergic disease in adulthood, develops initially during childhood. However, there is little information available on the kinetics of these early responses, or on the pattems of cytokine production during this period. Objective The purpose of this study was twofold: to obtain further information on the reported differences between responses to food versus inhalant allergens during early childhood, and to ascertain the age-range over which T-cell respon.ses to inhalant allergens become polarized towards the TH2 cytokine profile, in potentially atopic children. Methods In vitro cytokine responses to house dust mite (HDM) and egg (OVA) were assessed by semiquantitative RT-PCR in panels of 2- and 5-year-old children and adults; lymphoproliferative responses to OVA were subjected to epitope analysis. Results At age 2 years IL-4/IL-5 responses to HDM grouped with positive atopic family history, and by age 5 years cytokine responses correlated strongly with individual SPT reactivity to HDM. In contrast. OVA responses were restricted to weak and transient IL-5 signals in the 2-year-old family history positive group. Lymphopro life rat ion assays performed in parallel indicate a log-scale greater postnatal expansion of T-cell reactivity to the inhalant allergen; preliminary epitope analysis of OVA responses indicate that the number of OVA epitopes recognised decrease during early childhood. Conclusions Inhalant allergen-specific in vitro cytokine production associated with positive skin-prick test (SPT) reactions, one of the hallmarks of adult atopy, manifests in children at or before 5 years of age; additionally, cytokine responses in SPT negative 5 year-olds are restricted to IFNγ, as per normal adults. In contrast. T-cell responses to a typical food allergen appear to be deleted during early childhood. [ABSTRACT FROM AUTHOR]

Background Increasing evidence suggests that patterns of T-cell immunity to inhalant allergens in genetically diverse human populations are more heterogeneous than previously assumed, and that covert differences in expression patterns might underlie variations in airway disease phenotypes. We tested this proposition in a community sample of children. Methods We analysed data from 172 individuals who had been recruited antenatally to a longitudinal birth cohort study. Of the 194 birth cohort participants, data from the 147 probands (age range 8·6--13·5 years) who consented to blood collection were included along with data from 25 consenting siblings (mean age 11 years [range 7·4--17·4]). We ascertained clinical phenotypes related to asthma and allergy. We measured T-cell responses to allergens and mitogens, together with blood eosinophils and IgE/IgG antibodies, and assessed associations between these indices and clinical phenotypes. Findings Atopy was associated with allergen-specific T-helper (Th)2 responses dominated by interleukin 4, interleukin 5, interleukin 9, interleukin 13, whereas interleukin 10, tumor necrosis factor α, and interferon ϒ responses were common to both atopics and non-atopics. The wheal size from skin prick with allergen was positively associated with in-vitro interleukin 5 and interferon responses, and negatively associated with interleukin 10. Asthma, especially in atopics, was strongly associated with eosinophilia/interleukin 5, and bronchial hyper-responsiveness (BHR) was associated with eosinophilia plus polyclonal interferon ϒ production. BHR in non-atopics was associated with elevated allergen-specific and polyclonal interleukin 10 production. Interpretation Parallel immunological and clinical profiling of children identified distinctive immune response patterns related to asthma and wheeze compared with BHR, in atopics non-atopics. Immunological hyper-responsiveness... [ABSTRACT FROM AUTHOR]

Background: Recent findings suggest that a hallmark of the atopic phenotype is reduced capacity to respond to vaccine antigens, as well as to environmental allergens, during infancy. This deficiency, which is most marked for the cytokine IFN-gamma, appears transient but can result in a long-lasting imbalance within T helper cell (T(H)) memory responses to allergens. Indirect evidence suggests that parallel effects may occur within immunologic memory responses against vaccine antigens in atopic children., Objective: Our purpose was to compare vaccine antigen-specific T(H) memory responses in atopic and nonatopic children., Methods: We analyzed specific serum IgG and cytokine responses to pertactin and tetanus antigens as well as to mitogen (PHA) and house dust mite (HDM) allergen in 25 HDM-sensitized atopic and 25 nonatopic 6-year-old children who were vaccinated and boosted with diphtheria-tetanus-pertussis (DTP) vaccine., Results: PBMCs from the atopic subjects produced higher levels of T(H)1 and T(H)2 cytokines to HDM allergen and PHA. Vaccine antibody titers were normal in the atopic subjects; vaccine-specific T(H)2 responses were rarely detectable, yet T(H)1 (IFN-gamma) responses, in particular against tetanus, were frequent and higher in the atopic subjects (121.5 [SE 64.3] vs 8.0 [3.5] pg/mL culture fluid, P =.04). Corresponding pertactin responses were comparable in both groups., Conclusions: At the completion of the full primer-booster DTP vaccination regimen, levels of vaccine-specific immunity in atopic 6-year-old children are at least equivalent to their nonatopic counterparts, indicating that the transient atopy-associated deficiency in T(H)1 function in childhood can be successfully overcome by appropriate vaccination and boosting regimens.

The neonatal T-cell system is capable of responding to allergens at birth, indicating the occurrence of prenatal sensitization, and the cytokine profile of these responses is skewed towards the Th-2 type. This response is further modified by postnatal exposure to different types of allergens. In relation to inhalant allergen (employed by HDM) the low level fetal Th-2 responses in non-atopics appear to be down-regulated rapidly after birth, parallel to an increase in allergen-specific IFN-gamma production. In contrast, atopics appear to consolidate their initial Th-2 responses, and around the age of 6 exhibit a cytokine response profile similar to the adult pattern. A pre-existing deficiency in IFN-gamma production may be one of the key factors determining the postnatal persistence of Th-2 responses in atopics.