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Division of Cell Biology, TVW Telethon Institute for Child Health Research, Perth, Western Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One of the central enigmas of the allergy literature is the concept of the "sensitization window" during infancy. This concept derives from a wide body of epidemiology literature (reviewed in 4 indicating that early postnatal exposure to high levels of allergen, exemplified by "birth during the pollen season," maximizes the risk for subsequent expression of allergic reactivity to that allergen in adult life. This suggests that allergen challenge of the immune system during infancy predisposes the child toward development of long term Th2-skewed allergen-specific immunologic memory. Additionally, the available evidence suggests that this risk is highest for children with atopic parents or siblings, i.e., for those with the atopic genotype (5).
Recent findings relating to the postnatal development of immune
function have provided one possible explanation for this phenomenon. It
has been demonstrated in a series of independent studies that PBMC from
infants (6) and neonates (7, 8, 9, 10, 11) with positive atopic family histories
have a diminished capacity for secretion of Th1 cytokines (in
particular IFN-
) relative to their family history-negative
counterparts, and it has been suggested that delayed postnatal
maturation of this important aspect of cellular immune function may be
a key determinant of genetic predisposition to atopic disease (6, 12).
Consistent with this general postulate, a recent retrospective study (13) has demonstrated that expression of atopy in 12-yr-old children is most prevalent among those who had previously failed to develop Th1-dependent delayed tuberculin hypersensitivity in response to bacillus Calmette-Guérin (BCG) vaccination during infancy. Related to this issue, prospective seroepidemiologic studies on individual children (reviewed in 14 indicate that serum Ab responses against environmental allergens typically commence within a few months of birth, consistent with the initiation of primary immune responses as the naive immune system encounters these stimuli for the first time; a transient deficiency in Th1-related functions of the type reported (13) may accordingly increase the likelihood of selection for Th2-skewed memory during these early responses.
However, one further line of recent evidence suggests that there may be additional complexities in this process. Notably, low level lymphoproliferative responses to both inhalant and food allergens have been reported in cord blood (CB)3 (8, 15, 16), suggesting that initial priming of allergen-specific T cell responses may occur before birth. However, these claims are not universally accepted, as the origin of the putative allergen-reactive T cells in CB has not been formally established (for example, they may be of maternal origin), and there are no significant data on relevant T cell effector functions. The present study addresses these and related questions employing umbilical cord samples from 60 neonates, either with or without a family history of allergy, and for the first time provides formal proof of the fetal origin of the responding T cells as well as a comprehensive picture of their respective cytokine profiles.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The study was approved by the Princess Margaret Hospital Ethics
Committee (Perth, Western Australia). The CB donors were classified as
genetically at high risk (HR) or low risk (LR) for allergy on the basis
of a standardized questionnaire answered by the mothers, HR being
defined as 
1 first-degree relative with a positive allergy
history (6, 17).
Preparation and stimulation of cord blood mononuclear cells (CBMC)
CB samples were collected after obtaining informed consent from
the respective mothers. Collection was performed by inserting a
19-gauge needle into the placental vein, after careful swabbing with
alcohol to remove all contaminating maternal blood. CBMC were cultured
in triplicate for 7 days in microwells at 106 cells/ml
in serum-free medium as detailed (18), either alone or in the presence
of one of the following stimuli: unfractionated house dust mite
allergen (HDM) extract (10 µg/ml), unfractionated rye grass pollen
extract (WRE; 10 µg/ml), Fel d 1 allergen (30 µg/ml), OVA (100
µg/ml), ß-lactoglobulin (10 µg/ml), or tetanus toxoid (0.5
Lf/ml); these concentrations were identified as optimal for in vitro T
cell stimulation in preliminary experiments. DNA synthesis was measured
as incorporation of [3H]thymidine at the 7-day time
point, after pulse labeling at 6 days. Data were expressed as 
dpm
per culture, designating levels of incorporation above background
(unstimulated) control cultures. Responses that were >2x background
and >1000 dpm above background were considered positive (18).
To control for the potential stimulatory effects of LPS contamination in allergen extracts, a series of parallel studies was performed comparing allergen stimulation of CBMC in the presence and absence of polymyxin B at levels that blocked PBMC stimulation by 100 ng/ml LPS.
In a separate series of experiments, CD4+ T cells were
prepared from resting and allergen-stimulated CBMC employing
CD4+ Dynabeads (Dynal M-450; Dynal, Oslo, Norway) used at a
bead:cell ratio of 4:1, and purified CD4+ cells were
subsequently released from the beads using Dynal Detach-a-bead reagent
as per the manufacturer’s instructions. The cellular content of the
CD4- and CD4+ fractions were monitored by flow
cytometry, employing fluorochrome-conjugated anti-CD3,
anti-CD4, and anti-HLA-DR. Where specified below, cell
fractions were cultured with or without allergen, either alone or after
recombination at various ratios.
Epitope analysis of CBMC response to OVA
A series of 28 sequential overlapping peptides spanning the OVA molecule, comprising 19 mers overlapping by 5, was synthesized. They were pooled in (sequential) sets of three and introduced into replicate microcultures at final individual concentrations of 10 µg/ml. [3H]DNA synthesis was determined after 7 days, and individual responses were scored as positive/negative as described above.
Derivation and DNA typing of allergen-specific CBMC clones
T cell clones specific for the HDM of OVA allergen were derived from CB samples by methods based on those described previously (19). Briefly, allergen-induced T cell blasts were harvested from day 6 OVA- or HDM-stimulated cultures and cloned by limiting dilution in Terasaki microplates in the presence of X-irradiated heterologous splenocytes as feeder cells. Selected clones were expanded by polyclonal stimulation, rested, and retested for allergen specificity in a standard lymphoproliferation assay system using X-irradiated homologous T cell-depleted CBMC as APC, employing an unrelated Ag as control. The allergen-specific clones were cryopreserved until required for typing. For the latter procedure, genomic DNA was extracted into phenol-chloroform from parallel samples of 1) the clones, 2) PBMC taken from the mother of the original CB donor, and 3) PBMC from the CB donor at age 6 mo. One hundred nanograms of DNA was amplified by PCR using fluorescence-labeled primers for two loci. Data are reported herein for the ACTBP2 locus (actin-binding protein microsatellite (20)). The PCR products were separated by electrophoresis in a 6% acrylamide sequencing gel, and the individual fragments were visualized by fluorescence and computer-assisted scanning.
Allergen-specific cytokine responses of CBMC
CBMC were cultured for 24 h in medium alone or in medium
supplemented with optimal stimulating concentrations of HDM or OVA
allergen. Supernatants were assayed for the presence of IL-6, IL-10,
and IL-13 employing commercial ELISA kits (CLB Laboratories, Amsterdam,
The Netherlands). For cytokines produced at lower levels (IL-4, IL-5,
IL-9, and IFN-) together with ß-actin, specific mRNA was measured
in cell pellets by standardized semiquantitative RT-PCR as
described (21).
Briefly, RNA was extracted from cell pellets using RNAzol B, and cDNA
was transcribed using oligo(dT)15 and avian myeloblastosis virus
reverse transcriptase in the presence of ribonuclease inhibitor. The
PCR reactions, employing primers specific for IL-4, IL-5, IL-9,
IFN-, and ß-actin plus Tth plus (Biotech, Western
Australia) polymerase, were performed in a programmable thermocycler
(Perkin-Elmer, Norwalk, CT). Individual cycle analyses were performed
with each primer set, and cycle numbers were chosen that were in the
linear phase of the respective amplification reactions. Verification of
the expected size of the PCR products was obtained by analysis in 1.5%
agarose gels. Samples of the PCR products were manually dot-blotted
onto nylon membranes and hybridized overnight with biotinylated
double-stranded probes; binding was visualized by chemiluminescence
using a commercial kit (ECL western blotting reagents, Amersham
International Buckinghamshire, U.K.) (representative sample series
shown in Fig. 1
). Probe binding was
quantitated by computer-assisted densitometric scanning. The intensity
of each test sample was expressed as a ratio relative to that of its
respective ß-actin control.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CBMC responses to purified allergen preparations and tetanus
toxoid Ag are shown in Figure 2. The
majority (83%) of these 60 normal term fetuses show positive
lymphoproliferative responses to one or more common allergens. The most
frequent responses were to whole HDM extract (46%), ß-lactoglobulin
(44%), and OVA (42%). A proportion of samples also responded to Rye
allergen (24%) and Fel d 1 allergen from cat (22%). A subset of the
samples was tested with purified Der p 1 (the major allergen from HDM),
and 73% displayed positive responses (not shown). Only 3% showed any
response to tetanus toxoid. There was no difference in the frequency of
positive responses in HR and LR samples at birth; however, the median,
mean, and range of responses to all allergens were higher in the HR
group, although these differences were not statistically significant
using nonparametric tests.
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2 of these
peptide pools (Fig. 3), each of which
contain multiple OVA epitopes. In a smaller follow-up series of 7 CBMC
samples containing sufficient cells to test the full range of OVA
peptides individually, an average of six peptides was recognized
per CBMC (data not shown). This suggests that these fetal immune
responses involve recognition of multiple regions within the OVA
molecule and are thus likely to be directed against the native Ag, as
opposed to a small number of epitopes in a cross-reacting Ag.
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address
the hypothesis that CBMC preparations manifesting allergen-specific
lymphoproliferative responses contain fetal T cells that exhibit the
same Ag specificity. To test this hypothesis, T cell clones were
derived from lymphoblasts harvested from bulk cultures of CBMC that
were stimulated initially with OVA or HDM allergen and their respective
specificities confirmed by subsequent restimulation with allergen in
the presence of homologous APCs from cryopreserved stocks of T
cell-depleted CBMC. DNA extracted from the putative fetal clones was
compared with parallel samples from maternal cells and with PBMC from
the CMBC donor collected at age 6 mo, using microsatellite genotyping
at two polymorphic gene loci. Figure 4 demonstrates representative
results from one of the two loci tested, clearly illustrating the fetal
origin of the clones. Identical results were obtained via examination
of the amplified products of the second locus. These findings were
reproduced with an equivalent panel of clones from a second donor.
These data provide the first direct proof that allergen-specific T
cells in CBMC samples can be derived from the fetus and are not
necessarily the result of contamination with maternal cells.
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The principal focus of this study involved detailed analysis of cytokine production by allergen-stimulated CBMC in response to stimulation with the archetypal food allergen, OVA, and the archetypal inhalant allergen, HDM. Due to the expected low precursor frequency of allergen-reactive cells in these fetal responses, a minimum of 106 cells was used per test sample. Furthermore, in the light of the accumulating evidence that the selection of alternate pathways for Th cell differentiation during immune induction is markedly influenced by the cytokine milieu at the site of initial T cell activation, we elected to focus upon the 24-h time point after in vitro T cell stimulation.
The levels of IL-4, IL-5, IL-9, and IFN- protein produced in
these allergen-stimulated cultures were below the limits of detection
by commercially available ELISA, necessitating reliance upon RT-PCR for
semiquantification of specific mRNA. As shown in Figure 5, unequivocal up-regulation of mRNA
production specific for IL-4, IL-5, and IL-9 was frequently observed in
both LR and HR groups, employing 42 or 43 cycles for PCR. However, the
use of at least 47 cycles was required for detection of
allergen-induced IFN- signals, and IFN--specific mRNA
up-regulation was observed in only a small minority of
allergen-stimulated cultures (not shown). This finding contrasts with
our current experience in detecting equivalent IFN- responses in
5-year-old children and adults in whom 40 and 32 cycles, respectively,
are sufficient for specific mRNA detection (Ref. 21 and experiments in
progress).
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). However, these responses were
overshadowed by parallel IL-10 production in the same
allergen-stimulated cultures involving secretion of this cytokine at
levels up to 3000 pg/ml culture fluid. This high level of production of
IL-10 in allergen-stimulated bulk cultures was mirrored by results
obtained with specific T cell clones (Table I). At the completion of this series of
experiments, samples of supernatants from control and
HDM-stimulated cultures remained available from 35 members of the HR
group employed above. ELISA analysis of these supernatants indicated
allergen-specific up-regulation of IL-6 secretion in 24 of the 35
samples tested, which was highly significant at the population level
(Fig. 6). However, the clones produced no, or low levels of, IL-6,
suggesting that the IL-6 production seen in the bulk cultures of CBMC
may be from a non-T cell source. This possibility was further examined
in the experiments described below.
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Three sets of experiments were performed to address this issue, focusing upon cytokines produced in sufficient amounts to be measurable as protein. First, to assess the possible effects upon cytokine production of contaminating LPS in allergen samples, we stimulated a series of CBMC with 100 ng/ml of LPS, or OVA or HDM at the levels used above, in the presence or absence of 1 µg/ml polymyxin B. Supernatants were collected at 24 h and assayed for IL-6 and IL-10; the polymyxin B inhibited LPS-induced cytokine production but did not affect stimulation by the allergens (data not shown).
Second, purified CD4+ cells were separated from either
resting CBMC or from CBMC cultures after a 20-h stimulation with HDM or
OVA for further assessment of the relative roles of CD4+ T
cells vs other cell types in these cytokine responses. The
CD4+-enriched fractions used in the experiments below
comprised 92 to 95% CD3+/CD4+ T cells with
<2% HLA-DR+ cells, and the CD4- fraction
comprised 40 to 55% HLA-DR+ cells with <3%
CD4+ cells. In the experiments shown in Figure 7, CBMC were precultured overnight with
allergen before fractionation; the separated fractions were recultured
in fresh medium for a further 24 h and supernatants assayed for
cytokine. It is clear that IL-10 and IL-13 are exclusively produced by
CD4+ T cells in this system, whereas in contrast, >90% of
IL-6 production is attributable to the CD4- cell
fraction.
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employed alternative methodology, focusing upon HDM-induced production
of cytokines of potential monocyte origin, IL-6 and IL-10. In this
case, separation and recombination of CD4+ and
CD4- fractions were performed before allergen stimulation.
It is again clear that the CD4- fraction is capable of
high levels of HDM-induced IL-6 production; however, it also appears
that allergen-specific IL-6 production levels can be boosted markedly
in the presence of T cells (cf IL-6 by 80 x 103
CD4- cells vs 80 x 103 CD4-
T cells + 100 x 103 CD4+ T cells),
suggesting possible amplification of the CD4- IL-6
response via products from activated T cells. In contrast,
CD4- cells do not make IL-10 in response to HDM, but their
presence (presumably that of APCs) is required for the full T cell
response.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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), against which
the majority of adults in our population express active T cell immunity
(18). This observation, taken together with the data presented above on
DNA genotyping of allergen-specific T cell clones derived from
stimulated CBMC samples, argues that the T cells that are responsive to
these allergens in lymphoproliferation assays are of fetal as opposed
to maternal origin. More importantly, this study provides new
information on the underlying cytokine profiles in these fetal T cell
responses. The latter experiments examined allergen-induced cytokine
production at both the mRNA and (where feasible) protein level at
24 h poststimulation, to minimize the possibility of de novo
priming of T cells in the cultures and/or their in vitro
differentiation. Our results indicate that in contrast to the low level
IFN- response characteristic of the majority of normal (nonatopic)
adults (1, 2), the characteristic allergen-induced cytokine profile
among neonates comprises IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13,
suggesting a generalized skewing of these allergen-specific immune
responses toward the atopy-associated Th2 cytokine phenotype at
this age. It has not yet been established how these fetal responses are initiated, but one likely explanation is leakage of low levels of environmental allergens encountered during pregnancy (or peptides derived from them) across the placenta. Virtually all CB samples are rich in maternally derived IgG subclass Abs against common environmental allergens (22, 23), and the combination of the latter with an allergen may provide the initial signal for T cell priming. In this context, it is noteworthy that despite the presence of tetanus-specific IgG Abs in most CBs, tetanus-reactive T cells are rarely detected. Tetanus immunization during pregnancy is extremely uncommon, hence limiting the availability of relevant Ag to the fetus; significantly, when active tetanus immunization of pregnant women is performed, it results in tetanus-specific IgM production (indicative of the induction of primary immunity) in a high proportion of their offspring (24).
The finding that these fetal immune responses are dominated by Th2
cytokines is consistent with the recent literature indicating that the
immunologic milieu at the fetomaternal interface is constitutively
skewed away from Th1; this is believed to be an evolutionary adaptation
aimed at protecting the fetoplacental unit against the toxic effects of
cytokines such as IFN- (25, 26). It has been suggested that IL-10
production by mesenchymal cells within the placenta (23), in particular
trophoblasts (27), plays an important role in this process, and its
effects may be mediated via direct inhibition of IFN- production by
T cells and/or via suppression of the Th1-selective functions (notably
IL-12 production) of APCs (28, 29). These Th1-damping effects may be
amplified via the production by the placenta of high levels of
PGE2, which selectively inhibits IFN- production
(30, 31, 32), and further by local production of progesterone, which
stimulates IL-4 production (33, 34).
Accordingly, exogenous Ags that leak across the placenta are likely to
be presented to the fetal immune system within a milieu conducive to
positive selection for Th2 immunity. Moreover, the ultra-low levels of
Ag likely to cross the placenta are in the range that is also
preferentially stimulatory to Th2 cells (35), and the initial skewing
of fetal allergen-specific immune responses away from the Th1 cytokine
phenotype may thus be the result of the tandem operation of these two
factors. It is also of interest to note the high levels of
allergen-specific IL-10 production by fetal T cells primed in this
fashion (Fig. 6 and Table I), which may serve to reinforce this
Th2-polarization during subsequent restimulation driven by early
postnatal encounters with these allergens. In this context, high levels
of microenvironmental IL-10 during T cell activation have also been
demonstrated to promote anergy development, particularly in the
presence of potent T cell stimuli such as alloantigen (36), and a
similar mechanism may contribute to the postnatal regulation of T cells
to responses driven by direct stimulation with some environmental
allergens. One example of the latter may be responses to Ags present at
high concentrations in the diet, which typically peak during early
childhood and wane thereafter, suggesting the operation of underlying
negative control mechanism(s) (14, 16).
These findings have important implications for the etiology of atopic diseases. As noted above, early postnatal allergen exposure is a risk factor for development of long term, primary allergic sensitization, and the present study suggests that the basis for this risk may be the presence in the newborn of small populations of allergen-specific T cells that are primed during intrauterine life. This early Th2 priming, as described in recent murine models of neonatal tolerance (37, 38), is capable of deviating subsequent immune responses toward the selection of potentially pathogenic Th2-polarized memory.
The available epidemiologic evidence also indicates that the risk for
development of Th2-polarized memory against environmental allergens is
highest in subjects of the atopic genotype, i.e., those with a positive
atopic family history (5, 39). It is feasible that the latter may be a
reflection of the degree of polarization of initial allergen-specific
Th responses during fetal life; this possibility provided the impetus
for the LR:HR comparisons in the present study. While our observations
in Figure 5 show a general tendency toward higher allergen-specific
IL-5 and IL-9 responses within the HR population, the differences are
not consistent and may reflect the small size of the LR group. It is
pertinent to note in this context that several reports have
demonstrated that generalized capacity for IFN- production, as
measured in PHA stimulated cultures, is reduced in CBMC samples from HR
donors relative to those from LR subjects (7, 8, 9, 10, 11). This important issue
clearly requires a more detailed investigation to elucidate the
differences between individuals that relate to genetic background.
Additionally, this study highlights the potential importance of developmental factors associated with the postnatal maturation of overall immune competence in relation to the ultimate expression of the atopic phenotype. Thus, our results indicate that virtually all infants are born with their immune systems primed for the development of potentially pathogenic immunologic memory against environmental allergens, and yet resulting Th2-dependent allergic disease eventually manifests in only a minority of (atopic) subjects, as the majority eventually develops low level Th1-polarized memory to the same allergens (1, 2).
This implies that allergen responder phenotype is determined, to a substantial degree, by immune deviation involving allergen-driven T cell selection after birth, when the weakly primed neonatal immune system is confronted with (relatively) high levels of incoming allergens from the outside environment (14). This T cell selection process is dependent upon the functions of relevant APC. In the case of inhalant allergens, which are responsible for the bulk of atopic disease, the principal APC population involved are intraepithelial dendritic cells (DC), which occur as a dense network throughout the airway mucosa (40, 41, 42). It is noteworthy that this cellular network is poorly developed at birth and matures relatively slowly postnatally; during the preweaning period, the airway DC exhibit low MHC class II expression, poor APC function, and are refractory to inflammatory stimuli relative to the same cells in adults (4, 43, 44).
These latter findings are mirrored by recent reports on the role of DC in the neonatal tolerance phenomenon in mice, which have demonstrated that DC populations from central lymphoid organs in newborn animals are deficient in the capacity to prime naive T cells for Th1-dependent memory generation (37), resulting in a generalized skewing of immune responses during infancy toward the Th2-cytokine profile (37, 38, 45, 46). The capacity of human peripheral tissue DC to redirect neonatally primed T cell responses against environmental (particularly inhalant) allergens toward the nonatopic Th1 profile may, by analogy, be intrinsically low at birth and may additionally be further compromised by the high levels of IL-10 produced by these allergen-primed T cells during postnatal stimulation.
The precise role of APC in the postnatal maturation of Th1-associated
functions in humans has not yet been established. However, the
generalized poor in vitro performance of peripheral blood APC from
human infants has been recognized for some years (47). Moreover, the
results of in vitro cell mixing experiments suggest that the low
capacity of infant peripheral blood T cells to produce IFN- in
response to polyclonal stimulation is attributable, to a significant
extent, to a transient developmental defect in the costimulatory
function(s) of their endogenous accessory cells (48, 49), and
consequently, it appears that the parallels with the murine system may
be strong.
It is reasonable to speculate that the longer APC populations in human infants continue to express the neonatal functional phenotype during postnatal life, the greater will be the potential for consolidating allergen-specific Th2-polarized memory. The nature of the genetic and environmental factors that normally regulate the kinetics of postnatal development of DC remains to be elucidated, but a deeper understanding of the underlying mechanisms may provide novel opportunities for the primary prevention of these diseases, for example via hastening postnatal maturation of their Th1-stimulating functions. In this context, attention has recently been focused on the apparent inverse relationship between infections during early life and the subsequent expression of Th2-dependent allergy (5, 14, 50, 51, 52), and we speculate that these effects may be mediated in part via infection-driven stimulation of the Th1-associated immune functions of DC and other APC, such as IL-12 production.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. P. G. Holt, Division of Cell Biology, TVW Telethon Institute for Child Health Research, P.O. Box 855, West Perth WA 6872, Australia. E-mail address:
3 Abbreviations used in this paper: CB, cord blood; HR, high risk; LR, low risk; CBMC, cord blood mononuclear cell; HDM, house dust mite allergen; DC, dendritic cell.
Received for publication August 25, 1997. Accepted for publication January 12, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by cord-blood mononuclear cells is reduced in newborns with a family history of atopic disease and is independent from cord blood IgE-levels. Pediatr. Allergy Immunol. 4:60.[Medline]
secretion in neonates and subsequent atopy. Lancet 344:983.[Medline]
and decreased production of IL-6 by cord blood mononuclear cells of newborns with a high risk of allergy. Clin. Exp. Allergy 26:397.[Medline]
production by blood mononuclear cells in infancy with parental allergy skin tests and with subsequent development of atopy. J. Allergy Clin. Immunol. 96:652.[Medline]
-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041.-interferon by newborn cells in vitro is due to a functionally immature macrophage. J. Immunol. 134:1493.[Abstract]
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 D. J. Hartigan-O'Connor, K. Abel, and J. M. McCune Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression J. Exp. Med., October 29, 2007; 204(11): 2679 - 2692. [Abstract] [Full Text] [PDF]
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J. C. Horvat, K. W. Beagley, M. A. Wade, J. A. Preston, N. G. Hansbro, D. K. Hickey, G. E. Kaiko, P. G. Gibson, P. S. Foster, and P. M. Hansbro Neonatal Chlamydial Infection Induces Mixed T-Cell Responses That Drive Allergic Airway Disease Am. J. Respir. Crit. Care Med., September 15, 2007; 176(6): 556 - 564. [Abstract] [Full Text] [PDF]
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J. Yoo, H. Tcheurekdjian, S. V. Lynch, M. Cabana, and H. A. Boushey Microbial Manipulation of Immune Function for Asthma Prevention: Inferences from Clinical Trials Proceedings of the ATS, July 1, 2007; 4(3): 277 - 282. [Abstract] [Full Text] [PDF]
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 C. Hubeau, I. Apostolou, and L. Kobzik Targeting of CD25 and Glucocorticoid-Induced TNF Receptor Family-Related Gene-Expressing T Cells Differentially Modulates Asthma Risk in Offspring of Asthmatic and Normal Mother Mice J. Immunol., February 1, 2007; 178(3): 1477 - 1487. [Abstract] [Full Text] [PDF]
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M. Zemlin, G. Hoersch, C. Zemlin, A. Pohl-Schickinger, M. Hummel, C. Berek, R. F. Maier, and K. Bauer The Postnatal Maturation of the Immunoglobulin Heavy Chain IgG Repertoire in Human Preterm Neonates Is Slower than in Term Neonates J. Immunol., January 15, 2007; 178(2): 1180 - 1188. [Abstract] [Full Text] [PDF]
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 M. R. Goldberg, N. Luknar-Gabor, G. Zadik-Mnuhin, P. Koch, J. Tovbin, and Y. Katz Synergy between LPS and immobilized anti-human CD3{epsilon} mAb for activation of cord blood CD3+ T cells Int. Immunol., January 1, 2007; 19(1): 99 - 103. [Abstract] [Full Text] [PDF]
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 E K Chung, R L Miller, M T Wilson, S J McGeady, and J F Culhane Antenatal risk factors, cytokines and the development of atopic disease in early childhood Arch. Dis. Child. Fetal Neonatal Ed., January 1, 2007; 92(1): F68 - F73. [Abstract] [Full Text] [PDF]
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 P. S. Noakes, J. Hale, R. Thomas, C. Lane, S. G. Devadason, and S. L. Prescott Maternal smoking is associated with impaired neonatal toll-like-receptor-mediated immune responses Eur. Respir. J., October 1, 2006; 28(4): 721 - 729. [Abstract] [Full Text] [PDF]
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 T. Yamashita, S. Freigang, C. Eberle, J. Pattison, S. Gupta, C. Napoli, and W. Palinski Maternal Immunization Programs Postnatal Immune Responses and Reduces Atherosclerosis in Offspring Circ. Res., September 29, 2006; 99(7): E51 - E64. [Abstract] [Full Text] [PDF]
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C. Hubeau, I. Apostolou, and L. Kobzik Adoptively Transferred Allergen-Specific T Cells Cause Maternal Transmission of Asthma Risk Am. J. Pathol., June 1, 2006; 168(6): 1931 - 1939. [Abstract] [Full Text] [PDF]
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A. S. Leme, C. Hubeau, Y. Xiang, A. Goldman, K. Hamada, Y. Suzaki, and L. Kobzik Role of Breast Milk in a Mouse Model of Maternal Transmission of Asthma Susceptibility J. Immunol., January 15, 2006; 176(2): 762 - 769. [Abstract] [Full Text] [PDF]
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A. J. M. van Oosterhout and N. Bloksma Regulatory T-lymphocytes in asthma Eur. Respir. J., November 1, 2005; 26(5): 918 - 932. [Abstract] [Full Text] [PDF]
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 A Maitra, A Sherriff, K Northstone, D Strachan, the ALSPAC Study Team, and A J Henderson Maternal age of menarche is not associated with asthma or atopy in prepubertal children Thorax, October 1, 2005; 60(10): 810 - 813. [Abstract] [Full Text] [PDF]
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F. D. Martinez Heterogeneity of the Association between Lower Respiratory Illness in Infancy and Subsequent Asthma Proceedings of the ATS, August 1, 2005; 2(2): 157 - 161. [Abstract] [Full Text] [PDF]
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K. J. Aichberger, I. Mittermann, R. Reininger, S. Seiberler, I. Swoboda, S. Spitzauer, T. Kopp, G. Stingl, W. R. Sperr, P. Valent, et al. Hom s 4, an IgE-Reactive Autoantigen Belonging to a New Subfamily of Calcium-Binding Proteins, Can Induce Th Cell Type 1-Mediated Autoreactivity J. Immunol., July 15, 2005; 175(2): 1286 - 1294. [Abstract] [Full Text] [PDF]
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C. C. Obihara, B. J. Marais, R. P. Gie, P. Potter, E. D. Bateman, C. J. Lombard, N. Beyers, and J. L. L. Kimpen The association of prolonged breastfeeding and allergic disease in poor urban children Eur. Respir. J., June 1, 2005; 25(6): 970 - 977. [Abstract] [Full Text] [PDF]
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 B. Mommaas, J. A. Stegehuis-Kamp, A. G. van Halteren, M. Kester, J. Enczmann, P. Wernet, G. Kogler, T. Mutis, A. Brand, and E. Goulmy Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1 Blood, February 15, 2005; 105(4): 1823 - 1827. [Abstract] [Full Text] [PDF]
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A. E. Williams, L. Edwards, I. R. Humphreys, R. Snelgrove, A. Rae, R. Rappuoli, and T. Hussell Innate Imprinting by the Modified Heat-Labile Toxin of Escherichia coli (LTK63) Provides Generic Protection against Lung Infectious Disease J. Immunol., December 15, 2004; 173(12): 7435 - 7443. [Abstract] [Full Text] [PDF]
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C. A. Thornton, J. W. Upham, M. E. Wikstrom, B. J. Holt, G. P. White, M. J. Sharp, P. D. Sly, and P. G. Holt Functional Maturation of CD4+CD25+CTLA4+CD45RA+ T Regulatory Cells in Human Neonatal T Cell Responses to Environmental Antigens/Allergens J. Immunol., September 1, 2004; 173(5): 3084 - 3092. [Abstract] [Full Text] [PDF]
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E. W. Gelfand, A. Joetham, Z.-H. Cui, A. Balhorn, K. Takeda, C. Taube, and A. Dakhama Induction and Maintenance of Airway Responsiveness to Allergen Challenge Are Determined at the Age of Initial Sensitization J. Immunol., July 15, 2004; 173(2): 1298 - 1306. [Abstract] [Full Text] [PDF]
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A. R. O'Donnell, B. G. Toelle, G. B. Marks, C. M. Hayden, I. A. Laing, J. K. Peat, J. Goldblatt, and P. N. Le Souef Age-specific Relationship between CD14 and Atopy in a Cohort Assessed from Age 8 to 25 Years Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 615 - 622. [Abstract] [Full Text] [PDF]
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 J O Warner The early life origins of asthma and related allergic disorders Arch. Dis. Child., February 1, 2004; 89(2): 97 - 102. [Full Text] [PDF]
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V. E. Murphy, P. G. Gibson, W. B. Giles, T. Zakar, R. Smith, A. M. Bisits, C. G. Kessell, and V. L. Clifton Maternal Asthma Is Associated with Reduced Female Fetal Growth Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1317 - 1323. [Abstract] [Full Text] [PDF]
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B. Adkins Peripheral CD4+ Lymphocytes Derived from Fetal versus Adult Thymic Precursors Differ Phenotypically and Functionally J. Immunol., November 15, 2003; 171(10): 5157 - 5164. [Abstract] [Full Text] [PDF]
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 S. Rounioja, J. Rasanen, V. Glumoff, M. Ojaniemi, K. Makikallio, and M. Hallman Intra-amniotic lipopolysaccharide leads to fetal cardiac dysfunction: A mouse model for fetal inflammatory response Cardiovasc Res, October 15, 2003; 60(1): 156 - 164. [Abstract] [Full Text] [PDF]
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H. Uthoff, A. Spenner, W. Reckelkamm, B. Ahrens, G. Wolk, R. Hackler, F. Hardung, J. Schaefer, A. Scheffold, H. Renz, et al. Critical Role of Preconceptional Immunization for Protective and Nonpathological Specific Immunity in Murine Neonates J. Immunol., October 1, 2003; 171(7): 3485 - 3492. [Abstract] [Full Text] [PDF]
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A. Nowak-Wegrzyn, H. A. Sampson, R. A. Wood, and S. H. Sicherer Food Protein-Induced Enterocolitis Syndrome Caused by Solid Food Proteins Pediatrics, April 1, 2003; 111(4): 829 - 835. [Abstract] [Full Text] [PDF]
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P. A. Offit and C. J. Hackett Addressing Parents' Concerns: Do Vaccines Cause Allergic or Autoimmune Diseases? Pediatrics, March 1, 2003; 111(3): 653 - 659. [Abstract] [Full Text] [PDF]
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K. Hamada, Y. Suzaki, A. Goldman, Y. Y. Ning, C. Goldsmith, A. Palecanda, B. Coull, C. Hubeau, and L. Kobzik Allergen-Independent Maternal Transmission of Asthma Susceptibility J. Immunol., February 15, 2003; 170(4): 1683 - 1689. [Abstract] [Full Text] [PDF]
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N. Makori, A. F. Tarantal, F. X. Lu, T. Rourke, M. L. Marthas, M. B. McChesney, A. G. Hendrickx, and C. J. Miller Functional and Morphological Development of Lymphoid Tissues and Immune Regulatory and Effector Function in Rhesus Monkeys: Cytokine-Secreting Cells, Immunoglobulin-Secreting Cells, and CD5+ B-1 Cells Appear Early in Fetal Development Clin. Vaccine Immunol., January 1, 2003; 10(1): 140 - 153. [Abstract] [Full Text] [PDF]
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 J. W. Upham, P. T. Lee, B. J. Holt, T. Heaton, S. L. Prescott, M. J. Sharp, P. D. Sly, and P. G. Holt Development of Interleukin-12-Producing Capacity throughout Childhood Infect. Immun., December 1, 2002; 70(12): 6583 - 6588. [Abstract] [Full Text] [PDF]
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 C. Cole Johnson, D. R. Ownby, E. M. Zoratti, S. Hensley Alford, L. K. Williams, and C. L. M. Joseph Environmental Epidemiology of Pediatric Asthma and Allergy Epidemiol. Rev., December 1, 2002; 24(2): 154 - 175. [Full Text] [PDF]
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 J. Douwes and N. Pearce Asthma and the westernization 'package' Int. J. Epidemiol., December 1, 2002; 31(6): 1098 - 1102. [Full Text] [PDF]
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J. Heinrich, G. Bolte, B. Holscher, J. Douwes, I. Lehmann, B. Fahlbusch, W. Bischof, M. Weiss, M. Borte, and H-E. Wichmann Allergens and endotoxin on mothers' mattresses and total immunoglobulin E in cord blood of neonates Eur. Respir. J., September 1, 2002; 20(3): 617 - 623. [Abstract] [Full Text] [PDF]
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 T. A. E. Platts-Mills Paradoxical Effect of Domestic Animals on Asthma and Allergic Sensitization JAMA, August 28, 2002; 288(8): 1012 - 1014. [Full Text] [PDF]
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J P Legg, C A Jones, J A Warner, S L Johnston, and J O Warner A hypothesis: antenatal sensitisation to respiratory syncytial virus in viral bronchiolitis Arch. Dis. Child., June 1, 2002; 86(6): 431 - 433. [Abstract] [Full Text] [PDF]
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 A. E. Varner The Increase in Allergic Respiratory Diseases : Survival of the Fittest? Chest, April 1, 2002; 121(4): 1308 - 1316. [Abstract] [Full Text] [PDF]
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P.G. Holt and P.D. Sly Interactions between respiratory tract infections and atopy in the aetiology of asthma Eur. Respir. J., March 1, 2002; 19(3): 538 - 545. [Abstract] [Full Text] [PDF]
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M. T. Hopfenspirger and D. K. Agrawal Airway Hyperresponsiveness, Late Allergic Response, and Eosinophilia Are Reversed with Mycobacterial Antigens in Ovalbumin-Presensitized Mice J. Immunol., March 1, 2002; 168(5): 2516 - 2522. [Abstract] [Full Text] [PDF]
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H. Renz and U. Herz The bidirectional capacity of bacterial antigens to modulate allergy and asthma Eur. Respir. J., January 1, 2002; 19(1): 158 - 171. [Abstract] [Full Text] [PDF]
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R. L. MILLER, G. L. CHEW, C. A. BELL, S. A. BIEDERMANN, M. AGGARWAL, P. L. KINNEY, W. Y. TSAI, R. M. WHYATT, F. P. PERERA, and J. G. FORD Prenatal Exposure, Maternal Sensitization, and Sensitization In Utero To Indoor Allergens in an Inner-City Cohort Am. J. Respir. Crit. Care Med., September 15, 2001; 164(6): 995 - 1001. [Abstract] [Full Text] [PDF]
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J. E. Butler, J. Sun, P. Weber, S. P. Ford, Z. Rehakova, J. Sinkora, and K. Lager Antibody Repertoire Development in Fetal And Neonatal Piglets. IV. Switch Recombination, Primarily in Fetal Thymus, Occurs Independent of Environmental Antigen and Is Only Weakly Associated with Repertoire Diversification J. Immunol., September 15, 2001; 167(6): 3239 - 3249. [Abstract] [Full Text] [PDF]
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L. M. Bowman and P. G. Holt Selective Enhancement of Systemic Th1 Immunity in Immunologically Immature Rats with an Orally Administered Bacterial Extract Infect. Immun., June 1, 2001; 69(6): 3719 - 3727. [Abstract] [Full Text] [PDF]
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K. G. Tournoy, J. C. Kips, and R. A. Pauwels The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent J. Immunol., June 1, 2001; 166(11): 6982 - 6991. [Abstract] [Full Text] [PDF]
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H. Jyonouchi, S. Sun, T. Winship, and M. J. Kuchan Dietary Ribonucleotides Modulate Type 1 and Type 2 T-Helper Cell Responses against Ovalbumin in Young BALB/cJ Mice J. Nutr., April 1, 2001; 131(4): 1165 - 1170. [Abstract] [Full Text]
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J. K. Brieland, C. Jackson, F. Menzel, D. Loebenberg, A. Cacciapuoti, J. Halpern, S. Hurst, T. Muchamuel, R. Debets, R. Kastelein, et al. Cytokine Networking in Lungs of Immunocompetent Mice in Response to Inhaled Aspergillus fumigatus Infect. Immun., March 1, 2001; 69(3): 1554 - 1560. [Abstract] [Full Text] [PDF]
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 W. W. Busse and R. F. Lemanske Asthma N. Engl. J. Med., February 1, 2001; 344(5): 350 - 362. [Full Text] [PDF]
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S. Goriely, B. Vincart, P. Stordeur, J. Vekemans, F. Willems, M. Goldman, and D. De Wit Deficient IL-12(p35) Gene Expression by Dendritic Cells Derived from Neonatal Monocytes J. Immunol., February 1, 2001; 166(3): 2141 - 2146. [Abstract] [Full Text] [PDF]
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A.B. Kay Allergy and Allergic Diseases- First of Two Parts N. Engl. J. Med., January 4, 2001; 344(1): 30 - 37. [Full Text] [PDF]
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L. D. Mikus, L. A. Rosenthal, R. L. Sorkness, and R. F. Lemanske Jr. Reduced Interferon-{gamma} Secretion by Natural Killer Cells from Rats Susceptible to Postviral Chronic Airway Dysfunction Am. J. Respir. Cell Mol. Biol., January 1, 2001; 24(1): 74 - 82. [Abstract] [Full Text]
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N. Kanda and S. Watanabe Gangliosides GD1b, GT1b, and GQ1b Enhance IL-2 and IFN-{{gamma}} Production and Suppress IL-4 and IL-5 Production in Phytohemagglutinin-Stimulated Human T Cells J. Immunol., January 1, 2001; 166(1): 72 - 80. [Abstract] [Full Text] [PDF]
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J. K. Brieland, C. Jackson, S. Hurst, D. Loebenberg, T. Muchamuel, R. Debets, R. Kastelein, T. Churakova, J. Abrams, R. Hare, et al. Immunomodulatory Role of Endogenous Interleukin-18 in Gamma Interferon-Mediated Resolution of Replicative Legionella pneumophila Lung Infection Infect. Immun., December 1, 2000; 68(12): 6567 - 6573. [Abstract] [Full Text] [PDF]
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G. Walzl, S. Tafuro, P. Moss, P. J.M. Openshaw, and T. Hussell Influenza Virus Lung Infection Protects from Respiratory Syncytial Virus-Induced Immunopathology J. Exp. Med., November 6, 2000; 192(9): 1317 - 1326. [Abstract] [Full Text] [PDF]
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P. G. HOLT Antigen Presentation in the Lung Am. J. Respir. Crit. Care Med., October 1, 2000; 162(4): S151 - 156. [Abstract] [Full Text] [PDF]
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 E. L. Hurwitz Universal Childhood Vaccinations: A Faustian Bargain? Arch Pediatr Adolesc Med, October 1, 2000; 154 (10): 1063 - 1064. [Full Text] [PDF]
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 J. E. Snyder, N. M. Filipov, P. J. Parsons, and D. A. Lawrence The Efficiency of Maternal Transfer of Lead and Its Influence on Plasma IgE and Splenic Cellularity of Mice Toxicol. Sci., September 1, 2000; 57(1): 87 - 94. [Abstract] [Full Text] [PDF]
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U. HERZ, R. JOACHIM, B. AHRENS, A. SCHEFFOLD, A. RADBRUCH, and H. RENZ Prenatal Sensitization in a Mouse Model Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S62 - 65. [Full Text] [PDF]
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P. G. HOLT, C. MACAUBAS, S. L. PRESCOTT, and P. D. SLY Primary Sensitization to Inhalant Allergens Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S91 - 94. [Full Text] [PDF]
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F. D. MARTINEZ Viruses and Atopic Sensitization in the First Years of Life Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S95 - 99. [Full Text] [PDF]
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T. A. E. PLATTS-MILLS, K. BLUMENTHAL, M. PERZANOWSKI, and J. A. WOODFOLK Determinants of Clinical Allergic Disease . The Relevance of Indoor Allergens to the Increase in Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S128 - 133. [Full Text] [PDF]
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G. L. LARSEN and P. G. HOLT The Concept of Airway Inflammation Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S2 - 6. [Full Text] [PDF]
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P G Holt and P D Sly Paediatric origins of adult lung diseases bullet 2: Prevention of adult asthma by early intervention during childhood: potential value of new generation immunomodulatory drugs Thorax, August 1, 2000; 55(8): 700 - 703. [Full Text]
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C. A. JONES and P. G. HOLT Immunopathology of Allergy and Asthma in Childhood Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S36 - 39. [Full Text] [PDF]
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P. J. M. OPENSHAW and C. HEWITT Protective and Harmful Effects of Viral Infections in Childhood on Wheezing Disorders and Asthma Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S40 - 43. [Full Text] [PDF]
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J. Rowe, C. Macaubas, T. M. Monger, B. J. Holt, J. Harvey, J. T. Poolman, P. D. Sly, and P. G. Holt Antigen-Specific Responses to Diphtheria-Tetanus-Acellular Pertussis Vaccine in Human Infants Are Initially Th2 Polarized Infect. Immun., July 1, 2000; 68(7): 3873 - 3877. [Abstract] [Full Text] [PDF]
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P. G. HOLT Key Factors in the Development of Asthma: Atopy Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S172 - 175. [Full Text] [PDF]
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J. A. DOUGLASS and R. E. O'HEHIR What Determines Asthma Phenotype? . Respiratory Infections and Asthma Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S211 - 214. [Full Text] [PDF]
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C. E Donovan and P. W Finn Immune mechanisms of childhood asthma Thorax, October 1, 1999; 54(10): 938 - 946. [Full Text]
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A. Marchant, T. Goetghebuer, M. O. Ota, I. Wolfe, S. J. Ceesay, D. De Groote, T. Corrah, S. Bennett, J. Wheeler, K. Huygen, et al. Newborns Develop a Th1-Type Immune Response to Mycobacterium bovis Bacillus Calmette-Guerin Vaccination J. Immunol., August 15, 1999; 163(4): 2249 - 2255. [Abstract] [Full Text] [PDF]
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R. J Wright, M. Rodriguez, and S. Cohen Review of psychosocial stress and asthma: an integrated biopsychosocial approach Thorax, December 1, 1998; 53(12): 1066 - 1074. [Full Text]
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 O. Vayrynen, V. Glumoff, and M. Hallman Regulation of surfactant proteins by LPS and proinflammatory cytokines in fetal and newborn lung Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L803 - L810. [Abstract] [Full Text] [PDF]
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