| | Prenatal versus postnatal sensitization to environmental allergens in a high-risk birth cohortReceived 14 November 2006; received in revised form 24 January 2007; accepted 15 February 2007. published online 06 April 2007. BackgroundThe timing of allergen sensitization is controversial, with conflicting evidence suggesting transplacental priming versus exclusively postnatal priming. Resolution of this question is important in relation to rational design of allergy prevention strategies, particularly the issue of allergen avoidance during pregnancy. ObjectiveTo elucidate the kinetics of sensitization in high-risk children during their first 2 years of life. MethodsWe prospectively studied house dust mite (HDM)–specific IgE and IgG4 antibody production and associated T-cell immunity in a cohort of 200 high-risk infants. Parallel antibody studies tracked responses against a broader panel of inhalant and dietary allergens including peanut. ResultsHDM-induced TH2 responses in PBMC from 6 months onward, particularly IL-4 and IL-5, correlated increasingly strongly with sensitization outcomes at 2 years, and a contrasting negative relationship was observed with IFN-γ response capacity. HDM-induced T-cell responses in cord blood, although common, were unrelated to subsequent sensitization. Transient HDM-IgE (and IgG4) production frequently peaked at 6 or 12 months before returning to baseline, which suggests the onset of protective tolerance. This finding contrasted with progressively increasing HDM-IgE titers in children sensitized by 2 years of age. Comparably contrasting patterns were observed in peanut-specific responses in sensitized versus nonsensitized children. ConclusionPriming of TH2 responses associated with persistent HDM-IgE production occurs entirely postnatally, as HDM reactivity in cord blood seems nonspecific and is unrelated to subsequent development of allergen-specific TH2 memory or IgE. Clinical implicationsThese findings question the scientific basis for existing recommendations for allergen avoidance by high-risk women during pregnancy. Perth and Subiaco, Australia, and Uppsala and Stockholm, Sweden Abbreviations used: CBMC, Cord blood mononuclear cell, HDM, House dust mite, HR, High risk, OD, Odds ratio, RTE, Recent thymic emigrant, SPT, Skin prick test Interest has increased in the potential control of diseases such as atopic asthma via prevention of sensitization to environmental allergens during early life. Accordingly, it is important to determine in the relevant high-risk (HR) groups, the time frame over which priming against such allergens most frequently occurs. In this regard, a variety of data links risk for sensitization to seasonal allergens to birth in spring,1, 2, 3, 4 and this has been widely interpreted as evidence for active priming of the immune system in early postnatal life. However, it has also been shown that priming to some perennial and/or food allergens displays a similar season-dependent pattern,5 which suggests that other more complex mechanisms may underlie this association. It has additionally been suggested on the basis of allergen-induced T-cell reactivity in cord blood6, 7, 8, 9, 10 that sensitization can also occur transplacentally. Supportive data for such a mechanism include the cloning of allergen-reactive T-cells from cord blood and their subsequent genotyping to confirm fetal origin.10 The mechanism(s) underlying putative prenatal sensitization are unclear, but it could involve transplacental transport of immunogenic allergen fragments or IgG/allergen complexes.11, 12, 13 Several precedents exist for such fetal priming,14, 15 including the demonstration that maternal vaccination can trigger fetal antibody class switching.16 These and additional epidemiologic findings have prompted recommendations from the United Kingdom Committee on Toxicity of Chemicals in Food (COT)17, 18 and the New Zealand Ministry of Health19 for avoidance of peanut products by pregnant atopic women and a related (albeit milder) caution from the American Academy of Pediatrics.20 Moreover, they have stimulated a range of intervention studies aimed at prevention of food allergy via maternal avoidance of dietary allergens,21, 22, 23, 24 and similar approaches are being followed with respect to inhalant allergy.25, 26 However, the concept of fetal sensitization has been challenged, notably on the grounds of a lack of a quantitative relationship between maternal allergen exposure and T-cell responses in their newborn offspring.27, 28 Moreover, a recent expert review29 has questioned the clinical evidence for a protective effect of maternal allergen avoidance. Despite this question, the COT recommendations have not changed, and it is unclear how these guidelines and the associated debate have impacted on the community at large.22 A need for definitive evidence exists to help in finally resolving this controversial issue. The current study has addressed a series of immunologic questions relevant to this debate, focusing in particular on the relationship between priming of the specific TH cells responsible for driving immunoglobulin class switching and the ensuing production of specific IgE antibody. Our approach involves sampling a cohort of subjects at HR of atopy at regular intervals from birth to age 2 years, tracking the development of T-cell immunity and associated antibody production against the archetypal inhalant allergen house dust mite (HDM), with parallel analyses on IgE/IgG4 responses to a panel of additional inhalant and food allergens including peanut. Methods  Subjects were part of an ongoing prospective birth cohort of HR children as previously described.30 All aspects of the study were approved by our institutional Human Ethics Committee. At birth and at 6, 12, and 24 months of age, peripheral blood was collected. In addition, the children were assessed for skin prick test (SPT) reactivity to a standard panel of allergens comprising HDM (Dermatophagoides pteronyssinus), perennial rye, cat pelt, Alternaria tenuis, Aspergillus fumigatus, cow's milk, and hen's egg (Hollister-Stier, Spokane, Wash) at 6 and 24 months as performed previously.31 Antibody assays Antibody titers were determined via the ImmunoCAP 100 assay (Phadia AB, Uppsala, Sweden) as described for IgE32, 33 and IgG434 (detection limits 0.35 kU/L and 0.15 mg/L, respectively). In light of earlier suggestions of the potential usefulness of data on IgE levels in young children below the standard clinical cut-off of 0.35 kU/L,35, 36 a zero control was included in the IgE ImmunoCAP assay, which extended the limits of detection to 0.1 kU/L.37, 38 Additionally, cumulative titers of IgE and IgG4 against a panel of allergens (hens egg, cows milk, peanut, shrimp, D pteronyssinus, cat, dog, birch, timothy, ragweed, and wall pellitory [Parietaria judaica]), designated in text below as “polyclonal,” were determined via the Phadiatop Infant versions of ImmunoCAP.39 Cell preparation and culture Cord (CBMCs) and peripheral blood mononuclear cells (PBMCs) were isolated and cryopreserved for later batch analysis.40 CBMCs or PBMCs were cultured for 48 hours alone or with HDM or phytohemagglutinin (PHA) as performed previously.40 The HDM preparation was devoid of detectable lypopolysaccharide-like activity as per earlier studies.40 Cell pellets were resuspended into RNAlater (Ambion, Austin, Tex) and stored at –20°C until extraction (RNAqueous 96 kit, Ambion). Cytokine detection Cytokine protein levels above background were determined in supernatants by time-resolved fluorescence40 (TRF; limits of detection 10 pg/mL); cytokine-specific mRNA was determined by quantitative polymerase chain reaction (PCR) and normalized against the housekeeping gene UBE2D2.41 Statistical analysis Group differences were assessed via the Mann-Whitney U test and differences between individuals over time by the Wilcoxon matched pairs signed-rank test. Correlations between HDM SPT wheal size/IgE titers and immunologic outcomes were determined using the Kendal τ rank correlation. For multiple stepwise linear regression, and stepwise logistic regression, cytokine and antibody responses were log transformed, with values below the limits of detection (including zero values) being designated as half the limits of detection. Results Development of T-cell immunity to HDM allergen Fig 1 illustrates PBMC responses to HDM among HR infants stratified by HDM-SPT reactivity at age 2 years, measured via PCR. CBMCs from the majority (overall 72%) of subjects displayed 1 or more positive cytokine response to HDM, and respective IL-9, IL-13 and IFN-γ responses were often higher in CBMCs than in later infant samples. Parallel analyses of cytokine protein were also performed employing TRF; these data were highly correlated with respective mRNA (IL-5 Kendal τ rank .426, P = .000; IL-13: .448, P = .000; IFN-γ: .436, P = .000), but the PCR methodology was overall more sensitive and consistent in discriminating atopic and nonatopic groups, and hence, ensuing analyses (except Table I) use the latter. | | |  | | | Protein | mRNA | |
|---|
| Sample time | Statistic | IL-5 | IL-10 | IL-13 | IFN-γ | IL-4 | IL-5 | IL-9 | IL-13 | IFN-γ | |
|---|
| CB | Kendal τ rank correlation | 0.028 | 0.065 | 0.124 | 0.097 | −0.107 | 0.066 | 0.071 | 0.078 | 0.117 | | | | P value | .694 | .334 | .065 | .167 | .192 | .385 | .331 | .287 | .095 | | | 6 mo | Kendal τ rank correlation | 0.179 | −0.015 | 0.183 | 0.054 | 0.228 | 0.136 | 0.198 | 0.176 | 0.090 | | | | P value | .021 | .834 | .010 | .459 | .004 | .074 | .005 | .017 | .191 | | | 12 mo | Kendal τ rank correlation | 0.369 | 0.029 | 0.268 | 0.194 | 0.200 | 0.379 | 0.366 | 0.279 | 0.244 | | | | P value | .000 | .682 | .000 | .009 | .014 | .014 | .000 | .000 | .001 | | | | |
The most clear-cut distinction between cytokine responses in subjects grouped on the basis of HDM SPT status at 2 years were observed with respect to HDM-specific IL-4 and IL-5 outcome measures. Significant group differences are evident by 6 months for IL-4 and by 12 months for IL-5, and these differences follow predicted patterns (namely, relative TH2-polarity in the atopic group) and remain stable. Note also the progressive time-dependent increase in IL-4 responses in the SPT+ group. No CBMC cytokine responses displayed significant intergroup differences. Moreover, no allergen-specific HDM response in CBMC (protein or mRNA) correlated with later atopic status as measured by HDM-induced SPT wheal size at outcome age (Table I) or HDM-specific IgE titers (not shown). This result contrasted with a consistent pattern of positive correlations for the 6-month and particularly the 12-month samples. Postnatal development of HDM-specific IgE and IgG4 The HDM-specific response profiles for the overall study population are illustrated in Fig 2, A, stratified as in Fig 1 by SPT outcome. At the population level, HDM-specific IgE titers were significantly increased in the SPT+ group from 6 months onward and consolidated thereafter. The situation with respect to IgG4 was qualitatively similar. In particular, at 2 years, 44% of the HDM-SPT− children displayed measurable HDM-specific IgG4 titers, in contrast to 74% of the HDM-SPT+ group. Note also the high frequency of putative positive IgE readings, which are below the 0.35 kU/L clinical cut-off but above the 0.1 kU/L detection limits (particularly at 6 and 12 months) among the group who remains HDM-SPT–, the significance of which is discussed in more detail below. Fig 2, B tracks HDM-specific antibody in individuals over time. These assays were initially restricted to samples collected at and beyond 6 months, and 2 distinct response patterns were evident. Notably, HDM-specific IgE responses in children who were SPT+ at age 2 years typically trend progressively upward beyond 6 months, in marked contrast to those who were SPT–, the majority of whom tracked along the y-axis (below detection limits). However, a subpopulation of the subjects who were SPT– at outcome displayed transient low-level HDM-specific IgE responses that seemed to peak at either 6 or 12 months, trending down thereafter. Follow-up analyses on cord blood samples from the subset of subjects displaying 6-month titers greater than or equal to 0.1 kU/L (Fig 2, B) demonstrated that their HDM-specific IgE titers at birth were below this detection limit. This pattern is not evident for corresponding IgG4 responses. IgE and IgG4 responses at 6 months were not significantly related, but these responses were weakly correlated at 12 (Kendal τ rank correlation 0.146; P = .009) and 24 months (0.148; P = .004). Fig 3 illustrates corresponding patterns of IgE and IgG4 antibody titers against peanut, which mirror those for HDM, of particular note being the high frequency of children showing early transient “peak” peanut-specific IgE responses at 6 months; 90% of the latter remained low or continued to trend downward to 24 months (not shown). Comparable patterns were also observed for cat and grass (not shown). It is additionally pertinent to note that these fluctuating serum IgE responses were also accompanied by transient SPT responses; notably, 14 infants who displayed SPT reactivity to 1 or more allergens at the 6-month time point were completely SPT negative at 24 months (not shown). Fig 4 illustrates polyclonal antibody responses within the study population after stratification on the basis of overall atopic status at outcome age 2 years. Phadiatop Infant scores for both IgE and IgG4 increased progressively in the atopics over the observation period, which indicates generalized upregulation of TH2-dependent responses in this group. The relevant IgE scores were statistically increased at all time points in the atopics relative to the nonatopics (Fig 4, A), but this discrimination was not evident for IgG4. Tracking mixed allergen-specific IgE profiles in individual subjects by Phadiatop Infant (Fig 4, B) demonstrated biphasic patterns that were comparable with those observed in Fig 2, A for HDM-specific responses, but they were predictably more frequent as Phadiatop measures multiple specificities. At the population level, overall polyclonal IgE responses at 12 months are significantly increased relative to 6 months in both atopics and nonatopics, but they continued to rise thereafter only in the atopics (Fig 4, B). A biphasic response pattern can again be observed in a subset of subjects, for both IgE and IgG4. Total IgE increased progressively in both atopics and nonatopics, with the rate of climb being highest in the atopics (Fig 5). A subset of infants (n = 61) again displays an apparently biphasic pattern of overall IgE production, which shows titers that decline after 6 or 12 months of age. Relationships between cellular and humoral immune responses to allergens In parallel with the antibody studies, a series of analyses were carried out on corresponding cellular immune responses, which focus principally on HDM. Initial univariate analyses examined relationships between HDM-specific cytokine responses and corresponding IgE titers at the sampling times. No positive associations were observed before 2 years, presumably because of the low frequency of sensitized subjects producing specific IgE before this age (Fig 2, A). However, at 2 years, over 40 children were sensitized, and strong positive associations were evident within the overall cohort between their HDM-specific IgE titers and their HDM-induced TH2 cytokine responses, notably IL-4 (Kendal τ rank correlation 0.203; P = .001), IL-5 (0.260; P = .000), IL-9 (0.224; P = .000), and IL-13 (0.176; P = .004). Table II illustrates the results of logistic regression modeling of relationships between atopic reactivity to HDM and immune response variables at 6, 12, and 24 months. At the earliest sampling time (6 months), IL-4 responses to HDM were detectable in a subset of the study population, and positive responses at this time correlated strongly with having HDM-specific IgE antibody titers at 2 years above the 0.35 kU/L clinical cut-off for sensitization [odds ratio (OR) 11.8] and with a positive SPT reaction (OR 3.0). The frequency and magnitude of positive allergen-specific T-cell responses increased with age. By 12 months, IL-5 responses correlated positively with subsequent atopic outcomes at age 2 years, and IgE reactivity at 12 months showed a similar relationship. At outcome age itself, SPT reactivity correlated strongly with IgE titer, whereas having HDM-specific IgE titers above the clinical cut-off correlated strongly with the IL-9 component of the HDM-specific T-cell response. Of note, the TH1 response capacity at ages 1 and 2 years as measured by polyclonal (PHA) IFN-γ production correlated inversely with IgE responsiveness. | | | | Sample time | Outcome measure∗ | |
|---|
| 6 mo | Positive SPT response to HDM at 24 mo | IgE titer to HDM at 24 mo ≥ 0.35 kU/L | | | | IL-4/HDM (OR 3.093 [95% CI 1.091–8.764], P = .034) | IL-4/HDM (OR 11.847 [95% CI 3.568–39.332], P = .000) | | | 12 mo† | IL-5/HDM (OR 5.510 [95% CI 2.283–13.299], P = .000) | IFN-γ/PHA (OR 0.470 [95% CI 0.238–0.926], P = .029) | | | | IgE/HDM (OR 3.582 [95% CI 1.537–8.351], P = .003) | IL-5/HDM (OR 9.603 [95% CI 3.496–26.375], P = .000) | | | 24 mo | IgE/HDM (OR 6.893 [95% CI 3.868–12.282], P = .000) | IFN-γ/PHA (OR 0.326 [95% CI 0.127–0.833], P = .019) | | | | | IL-9/HDM (OR 3.644 [95% CI 2.279–5.828], P = .000) | | | | |
| ∗ Log HDM-specific mRNA and log PHA-stimulated protein cytokine levels are included in both models. HDM-specific log IgE and IgG4 are included in both models to predict SPT responsiveness. Confounding factors of gender, dual parental atopic history, and day care attendance in the first 2 years of life are included in each model. †Male gender (OR 7.705 [1.699–34.947], P = .008) and parental history (OR 5.137 [1.387–19.023], P = .014) were independently associated with IgE titer at 24 mo at this time point. |
These relationships are explored in more detail in Table III, which illustrates the results of multiple linear regression modeling of HDM-specific IgE and SPT responses at outcome age. Within the overall population, the IL-4, IL-5, and IL-9 components of the HDM-specific response were positively associated with IgE titers and the negative association observed with the TH1 cytokine IFN-γ in Table II was reiterated in this analysis. Among the atopic subset selected on the basis of IgE titers above the clinical cut-off, the strongest positive signals were observed for IL-5. The strongest determinant of HDM-specific SPT wheal size was the corresponding IgE titer, with an additional (weaker) signal from IL-5. With respect to HDM-specific IgG4, linear regression modeling demonstrated a significant relationship between serum titers at 24 months and in vitro HDM-specific IL-9 responses (t = 2.877; P = .004) and a negative relationship between 12 month titers and the IFN-γ component of the in vitro HDM response at the same time point (t = –2.142; P = .034). Discussion The scientific basis for recommending maternal allergen avoidance for prevention of infant sensitization rests primarily on the demonstration in cord blood of T cells that respond in vitro to allergens,7, 9, 10 inferring previous in utero priming. However, recent studies from our group have cast doubt on the phenotype of these cells. Notably, it is now evident that most putative TH-memory responses in neonates can be accounted for via the activity of recent thymic emigrant (RTE) CD4+ T cells expressing the naive CD45RA+ phenotype.42 These RTE cells express altered antigen receptors that lack the fine specificity of conventional T cells, and as a consequence, they can interact at low affinity with a broad range of antigens/allergens not previously encountered. T cells with comparably “promiscuous” antigen recognition properties have also been demonstrated in neonatal mice.43 An additional characteristic of the human neonatal RTE is that, after an initial round of allergen-triggered proliferation and cytokine production, they typically apoptose, unless “rescued” via high levels of cytokines such as IL-2.42 It is pertinent to note that a feature of the methodology in our earlier studies to generate allergen-specific T-cell clones from cord blood10 involved the use of high levels of IL-2, which accounts for their survival in the cloning cultures. If cord blood allergen-responsive T cells are indeed short-lived RTE as opposed to long-lived TH memory cells, it follows that specific allergen responsiveness in cord blood may be unrelated to subsequent allergen responder phenotype. Consistent with this conclusion: (1) HDM-induced IL-9, IL-13, and IFN-γ responses in cord blood display clear evidence of transience during infancy (Fig 1); and (2) the predicted patterns of positive associations between TH2 cytokine responses and subsequent sensitization outcomes, and parallel negative associations with TH1 responses, do not develop until at or beyond 6 months (Table I, Table II, Table III). Moreover, the broad concordance from 6 months and beyond between the kinetics of expansion of HDM-specific TH2 immunity, in particular relating to production in the atopics of IL-4, which drives IgE-B-cell switching (Fig 1 and Table II) and corresponding production of the TH2-dependent antibodies IgE and IgG4, provides a plausible and internally consistent argument that relevant T-cell and B-cell priming are both essentially postnatal processes. Additionally, postnatal tracking of IgE production in individual children who do versus who do not develop sensitization provides an additional level of information relating to the immunologic basis for natural resistance to allergy in nonatopic children. As illustrated in Fig 2, Fig 3, a significant proportion of children who remained nonatopic produced detectable levels of allergen-specific IgE that fluctuates within the low range, peaking in individual children at 6 or 12 months of age before returning to baseline, and this pattern is reiterated in total IgE levels (Fig 5) and, as noted, in patterns of SPT reactivity. These findings are consistent with earlier prospective studies,44 including those that have tracked nonatopic children beyond infancy to school age35, 45 and are consistent with animal model studies that have tracked the waxing and waning of specific IgE responses over prolonged periods of exposure to aeroallergens.46 The biphasic nature of IgE responses in these latter models is now recognized as the signature of an underlying process involving initial TH2-cell activation followed by development of protective immunologic tolerance,47 and a similar set of mechanisms is believed to operate in nonatopic humans during initial exposure to allergens, to prevent sensitization.48 The results presented here identify infancy/early childhood as the age range during which this protective mechanism commonly operates, and by extension as the logical life phase for implementation of intervention therapies aimed at enhancing the efficiency of this process, as suggested earlier.48 The latter approach is currently under trial in a double-blind placebo-controlled multicenter study in Australia and the United States focusing on HR infants and children.49 The principal implications of this study relate to the validity of current recommendations for dietary allergen avoidance by atopic women during pregnancy. Notably, our data refute the principal immunologic evidence underpinning these guidelines. The current study represents the most systematic analysis to date of the timing of allergen-specific immunologic priming, which focuses on HR infants who as a group are the most likely to manifest in utero sensitization, if such a process occurs. We have approached this issue by monitoring age-dependent changes in IgE/IgG4 and corresponding TH-cell cytokine responses, focusing in particular on HDM, with subsidiary analyses of additional IgE/IgG4 responses, including peanut and other specificities as pools measured via the Phadiatop Infant test. The broad consistency achieved between measures of TH2-polarized immunity and IgE/IgG4 responses, and the parallel negative association observed with TH1 reactivity, attest to the robustness of the methodology employed. On that basis, we argue that the finding of lack of association between cord blood T-cell reactivity to allergen and subsequent IgE or SPT responses, and the development of an increasingly strong association between these parameters beyond 6 months of age, suggests that the key events associated with development of the TH2-polarized allergen-specific memory that underpins stable atopic sensitization occurs postnatally as opposed to in utero. As such, and taken together with other recent data on the role of RTE in neonatal T-cell responses,42 we suggest that previous findings of putative allergen-responsive T cells in cord blood do not provide credible support for the notion of intrauterine sensitization, and as such add further weight to the doubts raised as to the validity of existing recommendations on maternal allergen avoidance.22 We stress that these findings pertain specifically to HR children and that applicability to the overall population remains to be determined. References 1. 1Bjorksten F, Suoniemi I. Dependence of immediate hypersensitivity on the month of birth. Clin Allergy. 1976;6:165–171. MEDLINE 2. 2Businco L, Cantani A, Farinella F, Businco E. Month of birth and grass pollen or mite sensitisation in children with respiratory allergy: a significant relationship. Clin Allergy. 1988;18:269–274. MEDLINE 3. 3Kihlstrom A, Lilja G, Pershagen G, Hedlin G. Exposure to high doses of birch pollen during pregnancy, and risk of sensitization and atopic disease is the child. Allergy. 2003;58:871–877. 4. 4Korsgaard J, Dahl R. Sensitivity to house dust mite and grass pollen. Clin Allergy. 1983;13:529–536. MEDLINE 5. 5Aalberse RC, Nieuwenhuys EJ, Hey M, Stapel SO. “Horoscope effect” not only for seasonal but also for nonseasonal allergens. Clin Exp Allergy. 1992;22:1003–1006. MEDLINE |
CrossRef
6. 6Hagendorens MM, Ebo DG, Bridts CH, Van de Water L, De Clerck LS, Stevens WJ. Prenatal exposure to house dust mite allergen (Der p 1), cord blood T cell phenotype and cytokine production and atopic dermatitis during the first year of life. Pediatr Allergy Immunol. 2004;15:308–315. MEDLINE |
CrossRef
7. 7Kondo N, Kobayashi Y, Shinoda S, Kasahara K, Kameyama T, Iwasa S, et al. Cord blood lymphocyte responses to food antigens for the prediction of allergic disorders. Arch Dis Child. 1992;67:1003–1007.
CrossRef
8. 8Miller RL, Chew GL, Bell CA, Biedermann SA, Aggarwal M, Kinney PL, et al. Prenatal exposure, maternal sensitization, and sensitization in utero to indoor allergens in an inner-city cohort. Am J Respir Crit Care Med. 2001;164:995–1001. 9. 9Piastra M, Stabile A, Fioravanti G, Castagnola M, Pani G, Ria F. Cord blood mononuclear cell responsiveness to beta-lactoglobulin: T-cell activity in “atopy-prone” and “non-atopy-prone” newborns. Int Arch Allergy Immunol. 1994;104:358–365. MEDLINE |
CrossRef
10. 10Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt PG. Development of allergen-specific T-cell memory in atopic and normal children. Lancet. 1999;353:196–200.
CrossRef
11. 11Casas R, Jenmalm MC, Bjorksten B. Cat allergen-induced cytokine secretion and Fel d 1-immunoglobulin G immune complexes in cord blood. Clin Exp Allergy. 2004;34:591–596. MEDLINE |
CrossRef
12. 12Holt PG, O'Keeffe PO, Holt BJ, Upham JW, Baron-Hay MJ, Suphioglu C, et al. T-cell “priming” against environmental allergens in human neonates: sequential deletion of food antigen specificities during infancy with concomitant expansion of responses to ubiquitous inhalant allergens. Pediatr Allergy Immunol. 1995;6:85–90. MEDLINE |
CrossRef
13. 13Vance GHS, Lewis SA, Grimshaw KEC, Wood PJ, Briggs RA, Thornton CA, et al. Exposure of the fetus and infant to hens' egg ovalbumin via the placenta and breast milk in relation to maternal intake of dietary egg. Clin Exp Allergy. 2005;35:1318–1326. MEDLINE |
CrossRef
14. 14Malhotra I, Mungai PL, Wamachi AN, Tisch D, Kioko JM, Ouma JH, et al. Prenatal T cell immunity to Wuchereria bancrofti and its effect on filarial immunity and infection susceptibility during childhood. J Infect Dis. 2006;193:1005–1013. 15. 15Marchant A, Appay V, van der Sande M, Dulphy N, Liesnard C, Kidd M, et al. Mature CD8(+) T lymphocyte response to viral infection during fetal life. J Clin Invest. 2003;111:1747–1755. MEDLINE |
CrossRef
16. 16Gill TJ, Repetti CF, Metlay LA. Transplacental immunisation of the human fetus to tetanus by immunisation of the mother. J Clin Invest. 1983;72:987–996. MEDLINE |
CrossRef
17. 17Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. Peanut allergy. London: Department of Health; 1998;. 18. 18Department of Health . Peanut allergy. London: Department of Health; 1998;. 19. 19Hannah ML. New Zealand Medicines and Medical Devices Safety Authority. Prescriber Update No. 20:22-26. Peanut Allergy. 2000. 20. 20American Academy of Pediatrics, Committee on Nutrition . Hypoallergenic infant formulas. Pediatrics. 2000;106:346–349. 21. 21Herrmann M-E, Dannemann A, Gruters A, Radisch B, Dudenhausen JW, Bergmann R, et al. Prospective study on the atopy preventive effect of maternal avoidance of milk and eggs during pregnancy and lactation. Eur J Pediatr. 1996;155:770–774. MEDLINE |
CrossRef
22. 22Turke J, Venter C, Dean T. Maternal experiences of peanut avoidance during pregnancy/lactation: an in-depth qualitative study. Pediatr Allergy Immunol. 2005;16:512–518. MEDLINE |
CrossRef
23. 23Vance GHS, Grimshaw KEC, Briggs R, Lewis SA, Mullee MA, Thornton CA, et al. Serum ovalbumin-specific immunoglobulin G responses during pregnancy reflect maternal intake of dietary egg and relate to the development of allergy in early infancy. Clin Exp Allergy. 2004;34:1855–1861. MEDLINE |
CrossRef
24. 24Zeiger RS, Heller S. The development and prediction of atopy in high-risk children: follow-up at age seven years in a prospective randomized study of combined maternal and infant food allergen avoidance. J Allergy Clin Immunol. 1995;96:1179–1190. 25. 25Custovic A, Simpson BM, Simpson A, Kissen P, Woodcock A. Effect of environmental manipulation in pregnancy and early life on respiratory systems and atopy during first year of life: a randomised trial. Lancet. 2001;358:188–193. Abstract | Full Text |
Full-Text PDF (89 KB)
|
CrossRef
26. 26Szépfalusi Z, Loibichler C, Pichler J, Reisenberger K, Ebner C, Urbanek R. Direct evidence for transplacental allergen transfer. Pediatr Res. 2000;48:404–407. MEDLINE 27. 27Björkstén B, Holt BJ, Baron-Hay MJ, Munir AKM, Holt PG. Low-level exposure to house dust mites stimulates T-cell responses during early childhood independent of atopy. Clin Exp Allergy. 1996;26:775–779. MEDLINE |
CrossRef
28. 28Platts-Mills TA, Blumenthal K, Perzanowski MS, Woodfolk JA. Determinants of clinical allergic disease. The relevance of indoor allergens to the increase in asthma. Am J Respir Crit Care Med. 2000;162:S128–S133. 29. 29Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part III: critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004;15:291–307. MEDLINE |
CrossRef
30. 30Rowe J, Poolman JT, Macaubas C, Sly PD, Loh R, Holt PG. Enhancement of vaccine-specific cellular immunity in infants by passively acquired maternal antibody. Vaccine. 2004;22:3986–3992.
CrossRef
31. 31Kusel MM, Holt PG, de Klerk N, Sly PD. Support for 2 variants of eczema. J Allergy Clin Immunol. 2006;116:1067–1072. Abstract | Full Text |
Full-Text PDF (119 KB)
|
CrossRef
32. 32Evans G, Rilven M. Bulk Reagent Random-Access analyzers: UniCAP 100. In: The Immunoassay Handbook. Frome, UK: Tradespools Ltd; 2000;. 33. 33Yman L. Allergy. The Immunoassay Handbook. Frome, UK: Tradespools Ltd; 2000;. 34. 34Cressy I, Magnusson B, Soderstrom L, Kober A. IgG4 antibody concentrations to cat and mite allergens measured with the new ImmunoCAP specific IgG4 method. In: Proc XXV Congress of the European Academy of Allergy and Clinical Immunology. Vienna: Austria; 2006;p. 296. 35. 35Hattevig G, Kjellman B, Björkstén B. Appearance IgE antibodies to ingested and inhaled allergens during the first 12 years of life in atopic and non-atopic children. Pediatr Allergy Immunol. 1993;4:182–186. MEDLINE |
CrossRef
36. 36Sasai K, Furukawa S, Muto T, Baba M, Yabuta K, Fukuwatari Y. Early detection of specific IgE antibody against house dust mite in children at risk of allergic disease. J Pediatr. 1996;128:834–840. Abstract | Full Text |
Full-Text PDF (838 KB)
|
CrossRef
37. 37Cain TW, Ford J, Dolen WK. A low-level method for measurement of specific immunoglobulin E antibody serum. Allergy Clin Immunol Int J World Allergy Org. 2006;18/6:1–4. 38. 38Wood RA, Segall N, Ahlstedt S, Williams PB. Not all IgE antibody laboratory results provide accurate information for clinical judgement. Ann Allergy 2007. In press. 39. 39Ballardini N, Nilsson C, Nilsson M, Lilja G. ImmunoCAP™ Phadiatop® Infant - a new blood test for detecting IgE sensitisation in children at 2 years of age. Allergy. 2006;61:337–343. 40. 40Heaton T, Rowe J, Turner S, Aalberse RC, de Klerk N, Suriyaarachchi D, et al. An immunoepidemiological approach to asthma: identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children. Lancet. 2005;365:142–149.
CrossRef
41. 41Strickland DH, Stumbles PA, Zosky GR, Subrata LS, Thomas JA, Turner DJ, et al. Reversal of airways hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T-cells. J Exp Med. 2006;203:2649–2660. MEDLINE |
CrossRef
42. 42Thornton CA, Upham JW, Wikström ME, Holt BJ, White GP, Sharp MJ, et al. Functional maturation of CD4+ CD25+ CTLA4+ CD45RA+ T regulatory cells in human neonatal T cell responses to environmental allergens. J Immunol. 2004;173:3084–3092. MEDLINE 43. 43Gavin MA, Bevan MJ. Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire. Immunity. 1995;3:793–800. MEDLINE |
CrossRef
44. 44Kulig M, Bergmann R, Klettke U, Wahn V, Tacke U, Wahn U. Natural course sensitization of food and inhalant allergens during the first 6 years of life. J Allergy Clin Immunol. 1999;103:1173–1179. Abstract | Full Text |
Full-Text PDF (160 KB)
|
CrossRef
45. 45Julge K, Vasar M, Björkstén B. Development of allergy and IgE antibodies during the first five years of life in Estonian children. Clin Exp Allergy. 2001;31:1854–1861. MEDLINE |
CrossRef
46. 46McMenamin C, Holt PG. The natural immune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cell-mediated but MHC class II-restricted CD4+ T cell-dependent immune deviation resulting in selective suppression of IgE production. J Exp Med. 1993;178:889–899. MEDLINE |
CrossRef
47. 47Holt PG, Sedgwick JD. Suppression of IgE responses following antigen inhalation: a natural homeostatic mechanism which limits sensitization to aeroallergens. Immunol Today. 1987;8:14–15.
CrossRef
48. 48Holt PG. A potential vaccine strategy for asthma and allied atopic diseases in early childhood. Lancet. 1994;344:456–458.
CrossRef
49. 49Holt PG, Sly PD. Prophylaxis of atopy and asthma in children. NIH Immune Tolerance Network Trial. 2006. Available at: http://www.immunetolerance.org/research/allergy/trials/holt.html. a From the Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth b Princess Margaret Hospital for Children, Subiaco c Phadia AB, Uppsala d Karolinska Institute, Stockholm  Reprint requests: Patrick G. Holt, DSc, Division of Cell Biology, Telethon Institute for Child Health Research, PO Box 855, West Perth WA 6872, Australia.
Supported by a grant from the National Health & Medical Research Council of Australia with supplementary support from the Food Allergy Initiative, New York. Disclosure of potential conflict of interest: L. Soderstrom and S. Ahlstedt are employed by Phadia AB, Uppsala, Sweden. The rest of the authors have declared that they have no conflict of interest. PII: S0091-6749(07)00412-5 doi:10.1016/j.jaci.2007.02.016 © 2007 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved. | |
|
FULL TEXT00412-5/journalimage?img=PIIS0091674907004125.gr1.lrg.gif&fig=fig1&kwhquery=&issn=0091-6749&ishighres=false&allhighres=false&free=yes','journalimage');)
00412-5/journalimage?img=PIIS0091674907004125.gr2.lrg.gif&fig=fig2&kwhquery=&issn=0091-6749&ishighres=false&allhighres=false&free=yes','journalimage');)
00412-5/journalimage?img=PIIS0091674907004125.gr3.lrg.gif&fig=fig3&kwhquery=&issn=0091-6749&ishighres=false&allhighres=false&free=yes','journalimage');)
00412-5/journalimage?img=PIIS0091674907004125.gr4.lrg.gif&fig=fig4&kwhquery=&issn=0091-6749&ishighres=false&allhighres=false&free=yes','journalimage');)
00412-5/journalimage?img=PIIS0091674907004125.gr5.lrg.gif&fig=fig5&kwhquery=&issn=0091-6749&ishighres=false&allhighres=false&free=yes','journalimage');)