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. 2001 Dec;126(3):390–396. doi: 10.1046/j.1365-2249.2001.01703.x

Influence of atopic heredity on IL-4-, IL-12- and IFN-γ-producing cells in in vitro activated cord blood mononuclear cells

S Gabrielsson †,*, A Söderlund †,*, C Nilsson ‡, G Lilja ‡, M Nordlund §, M Troye-Blomberg †
PMCID: PMC1906210  PMID: 11737052

Abstract

Several reports have claimed that there is a greater risk for a child with an atopic mother to develop allergy as compared to a child with an atopic father. This suggests that the fetal environment during pregnancy might be of importance for the development of atopic disease. Both proliferative and cytokine responses have been detected in cord blood mononuclear cells (CBMC) after stimulation with allergens, suggesting allergen priming already in utero. The aim of this study was to investigate whether the atopic status of the mother influences cytokine production by CBMC. We compared interleukin (IL)-4, IL-12 and interferon (IFN)-γ-producing CBMC from children with double atopic heredity (dh), maternal atopic heredity only (mh) or no atopic heredity (nh). CBMC were stimulated in vitro with allergens (birch, ovalbumin and cat), phytohaemagglutinin (PHA) or purified protein derivative (PPD) and cytokine-producing cells were measured by the enzyme-linked immunospot assay. In response to PHA, the frequency of IL-4-producing cells, as well as the ratio of IL-4/IFN-γ-producing cells, were significantly higher in the dh group compared to the nh group. High numbers of IL-12-producing cells in response to allergens were detected, significantly highest in the nh group, followed by the dh and mh groups. Our results suggest that there is a stronger Th2 bias after in vitro stimulation of CBMC from children with atopic heredity, as reflected by higher IL-4/IFN-γ ratios in response to PHA, and lower numbers of IL-12-producing cells after allergen stimulation. Whether these differences influence later allergy development will be evaluated when the atopic status of the children is assessed at 2 years of age.

Keywords: atopy, cord blood, IL-12, IL-4, IFN-γ

INTRODUCTION

During the past decades there has been a steady increase in the prevalence of allergic diseases. The reasons for this are largely unknown, but factors such as changes in pattern of childhood infections, gastrointestinal microflora, diet, indoor and outdoor environment have all been mentioned as potential influences. Several reports have shown that the initial priming of the immune system against both inhalant and food allergens occurs during the prenatal period, and that proliferative responses to allergens can already be detected in cord blood mononuclear cells (CBMC) [1–3]. A successful pregnancy is dependent upon a polarization from Th1 to Th2 responses in the mother since Th1 type of cytokines, such as interferon (IFN)-γ, are harmful to the placenta and fetus [4,5]. Th2 cytokines, such as IL-4, are more prominent in atopics compared to healthy individuals. Thus, one might speculate that an atopic mother could influence the fetus more strongly to develop Th2 responses leading potentially to allergy than a non-atopic mother. In line with this, there have been reports suggesting that an atopic mother confers a greater risk than an atopic father for the development of atopic disease in the child [6–8]. The maternal influence could be allergen-specific due to leakage of allergen, anti-idiotypic antibodies or allergen–antibody transfer across the placenta [9]. Alternatively, it could be non-specific through the cytokine environment at the materno–fetal interface, or be due to factors that the child encounters during the postnatal period, e.g. through breast milk [10–12].

Earlier studies have shown that CBMC from newborns with hereditary risk for atopy exhibit reduced IFN-γ production in response to mitogens [13,14]. In follow-up studies, the levels of IFN-γ were shown to be lower in CBMC from children who later developed atopy, in both phytohaemagglutinin (PHA)- [15,16] and allergen-stimulated [17] cells. A reduction in allergen-specific interleukin (IL)-13 levels has also been demonstrated in high risk children by Prescott et al. [18]. Moreover, in a later study by the same group, CBMC from children with atopic heredity who later developed atopic disease showed a lower production of most cytokines in response to house-dust mite compared to a non-atopic group. The IFN-γ production was low in both groups at birth, and it increased with age only in the non-atopic group [19]. Thus, all these data indicate a down-regulation of cytokine responses in CBMC from children who later developed allergy.

IL-12 is a cytokine that is potent in inducing Th1 responses. It is produced by antigen presenting cells (APC), dendritic cells (DC) and monocytes/macrophages, either after stimulation with bacterial cell wall products or after direct interaction with T cells via CD40/CD154 (CD40L). In the latter pathway, additional factors such as cytokines are also required for IL-12 production, the regulation of which is complex, since both IFN-γ [20] and IL-4 [21] have been shown to up-regulate bioactive IL-12. It has also been reported that IL-12 induces naive Th cells to produce IFN-γ during primary stimulation [22,23].

The hypothesis for this study was that atopic and non-atopic mothers differ regarding their in utero environment during pregnancy, which might influence the cytokine production by CBMC of the progeny. The IL-4, IL-12 and IFN-γ responses to inhalant (birch and cat) and food (egg) allergens, the mitogen PHA and the purified protein derivative (PPD) antigen were compared in CBMC from neonates with different atopic heredity [double atopic heredity (dh), maternal atopic heredity (mh) and no atopic heredity (nh)]. The results revealed that children with double atopic heredity displayed the highest IL-4/IFN-γ ratio after PHA stimulation, with a significant difference compared to the nh group. However, there was no difference between the mh and nh groups, suggesting that the atopic status of both parents is important for the production of these cytokines by CBMC. An additional finding was that following allergen stimulation, high numbers of IL-12-producing cells were induced. This was true for all three groups; however, the highest number of allergen-induced IL-12-producing cells was seen in CBMC from children without atopic parents.

MATERIALS AND METHODS

Subjects

Fifty-seven pregnant women were recruited from the maternity ward and the families were divided into three groups with different atopic heredity: (1) double heredity (dh, n = 20), (2) maternal heredity (mh, n = 18) or (3) no heredity (nh, n = 19). Venous blood samples for serological analysis were taken from the parents, where the sample from the mother was taken just before delivery of the child. The diagnosis of atopy was based on history of rhinoconjunctivitis or asthma and a positive skin prick test (SPT), the wheal reaction to the allergen being at least the size of histamine control (10 mg/ml). The allergens tested for were: dog, horse, rabbit, cat, birch, timothy grass, mugwort and, if required, moulds and house dust mite. The non-atopic parents were confirmed to be negative in SPT. There were no differences in the age of the mothers, the birth weight of the children or the number of siblings in the three different groups (not listed). The sampling of CB was distributed evenly over the year, with no differences between the groups. The study was approved by the Ethics Committee of Huddinge Hospital, Stockholm and the parents provided informed consent.

Reagents

The monoclonal antibodies used in the enzyme-linked immunospot assay (ELISpot) were for coating M-450 to human IL-4 (Endogen, MA, USA), MoAb 1-D1K to human IFN-γ and IL-12-I to human IL-12 p40 + p70 and for detection biotinylated MoAbs 12·1 (IL-4-II) to IL-4, 7-B6-1 to IFN-γ and IL-12-II to human IL-12 p40 + p70, all from Mabtech (Stockholm, Sweden). The specific allergens used were Aquagen-SQ birch and cat (32 × 103 SQ-U/ml, ALK, Hörsholm, Denmark) and ovalbumin (ova, 10 µg/ml Sigma, Stockholm, Sweden). The mitogen PHA (1 µg/ml, Murex Diagnostics Ltd, Dartford, UK) and PPD (1 µg/ml, Statens Serum Institute, Copenhagen, Denmark) served as control antigens.

Quantification of IgE

Allergen-specific IgE levels were measured in parental serum by CAP RAST FEIA (Pharmacia-Upjohn, Stockholm, Sweden) for birch, timothy grass, cat and dog (detection limit 0·35 kU/l). Total IgE levels in CB serum were detected by an ultra-sensitive CAP IgE FEIA [24] (Pharmacia-Upjohn, detection limit 0·1 kU/l) and in parent serum by the conventional CAP IgE FEIA (Pharmacia-Upjohn, detection limit 2 kU/l).

Preparation and stimulation of CBMC

CB samples were aspirated from the umbilical cord vein into heparinized Vacutainer tubes after careful wiping of the cord with alcohol. CBMC were isolated by Ficoll-Paque (Pharmacia-Upjohn) gradient centrifugation performed twice. The cells were frozen at 107 cells/ml in tissue-culture media (TCM = RPMI 1640-Hepes supplemented with gentamicin (25 µg/ml), 2 mm l-glutamine and 10% heat-inactivated fetal calf serum) containing 10% dimethyl sulphoxide (DMSO) and frozen gradually 1°C/min to −70°C in a freezing container (Nalgene Cryo 1°C, Nalge Company, USA), thereafter stored in liquid nitrogen. There were no differences in time between sampling and freezing of the isolated CBMC among the three groups. After thawing, the CBMC were cultured at 1 million cells/ml in TCM in a final volume of one ml in 5 ml-culture tubes (Falcon, Becton-Dickinson, New Jersey, USA) in the presence of allergen, PHA or PPD at concentrations previously shown to induce IL-4 and IFN-γ production [25]. The tubes were incubated at 37°C in a humid atmosphere containing 5% CO2 for 4 h. After this initial incubation the cells were resuspended, and thereafter transferred to ELISpot plates.

ELISpot

The reverse ELISpot assay was performed mainly as described previously [25]. Briefly, the antihuman-IL-4, IL-12 or IFN-γ MoAbs were added onto nitrocellulose plates (Millipore Corp., Bedford, MA, USA) at a concentration of 10 µg/ml in sterile, filtered carbonate buffer (pH 9·6). Plates were incubated overnight at 4°C, washed with filtered phosphate buffered saline (PBS, pH 7·2) and, in the last wash, the PBS was forced through the membrane with a vacuum control machine (Millipore). The preactivated cell suspensions (with the stimulant still present) were added in triplicate (100 000 cells per well), the plates incubated for 40 h at 37°C, 5% CO2, whereafter the cells were washed away and biotinylated MoAbs (1 µg/ml) were added, followed by an incubation for 2 h at room temperature (RT). Thereafter, the plates were washed and incubated for 90 min at RT with streptavidin–alkaline–phosphatase (diluted 1/1000, Mabtech). After another series of washings, BCIP/NBT substrate solution (Bio-Rad, Richmond, USA) was added and the plates were incubated at RT until dark spots emerged. The development was stopped by washings with water. After drying, the spots were counted in a dissection microscope ( × 40). All CB samples were tested for all cytokines except for one sample in the mh group, in which the IL-4 assay became over-developed.

Statistical analysis

The Mann–Whitney U-test was used to compare ELISpot results between the groups with different heredity. Correlations were tested with Spearman's rank test. The difference was considered significant if P <0·05. The mean ± s.d. is given in the text; the error bars in the figures correspond to s.e.m. The spontaneous cytokine production has been subtracted for all values shown.

RESULTS

IgE levels in adult and CB serum

The study groups were selected according to history of disease and SPT results. The specific serum IgE levels of the parents corresponded well to the history of disease and SPT results, except for two fathers in the mh group, who had low levels of allergen-specific IgE. The total IgE values are shown in Table 1. No statistically significant differences were seen when comparing CB IgE levels between the three groups. Atopic and non-atopic parents differed significantly in total IgE serum levels. Significant correlations between CB IgE and maternal total IgE levels were found in the dh and mh groups, but not in the non-atopic group (Fig. 1). No correlations were found between CB IgE and the total IgE of the father (not shown). Interestingly, the atopic mother with the highest total serum IgE level (1312 kU/ml) had a child with the highest level of total IgE in CB (16·4 kU/ml).

Table 1.

Subject characteristics

Total IgE (kU/l)
median range
dh mother 68·3 2·5–1312·0
father 126·0 14·4–955·0
cord 0·28 0·1–16·4
mh mother 76·2 5·0–864·0
father 28·1 2·5–80·3
cord 0·21 0·1–5·9
nh mother 12·5 2·0–229·0
father 29·3 3·3–248·0
cord 0·26 0·1–3·6
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dh, double atopic heredity, n = 20; mh, maternal atopic heredity, n = 18; nh, no atopic heredity, n = 19.

Fig. 1.

Fig. 1

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Correlation of CB IgE to maternal serum total IgE in three groups with different atopic heredity. (a) Double atopic heredity (dh, n = 20), correlation coefficient, r = 0·57, P < 0·05, (b) maternal atopic heredity (mh, n = 18), r = 0·70, P < 0·01, (c) no atopic heredity (nh, n = 19), r = 0·004; n.s. = not significant.

IL-4-producing cells in CBMC

The mean number of IL-4-producing cells in response to medium alone was 1·1 ± 1·2 spots/100 000 cells, and there were no differences between the groups. After allergen stimulation, the values were very low (e.g. for birch: 1·4 ± 1·4 spots above background). Similarly, in response to PPD, the numbers of IL-4-producing cells were low and did not differ between groups (1·5 ± 1·8 spots). However, after PHA stimulation, there was an induction of IL-4-producing cells, with significantly higher numbers in the dh group as compared to the mh group, which had the lowest numbers of IL-4-producing cells (P < 0·05, Fig. 2). No differences were seen between the dh and the nh groups, or the mh and nh groups.

Fig. 2.

Fig. 2

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Frequencies of IL-4-producing cells/100 000 CBMC in response to PHA (1 μg/ml) from children with different atopic heredity. ▪, dh = double heredity (n = 20), Inline graphic, mh = maternal heredity (n = 17), □, nh = no heredity (n = 19). Frequencies were measured in ELISpot in triplicate, spontaneous production subtracted and mean values ±s.e.m. are shown.

IFN-γ-producing cells in CBMC

In response to medium alone, the mean number of IFN-γ-producing cells was 2·8 ± 2·7, and no differences between the groups were detected. In response to allergens, IFN-γ-producing cells were induced, and tended to be highest in the nh group; however, no significant differences were found (Fig. 3). After PHA stimulation the pattern was similar to IL-4, where the mh group displayed the lowest number of IFN-γ-producing cells, with a significant difference to the dh and nh groups (P < 0·05 for both, Fig. 3). The numbers of IFN-γ-producing CBMC were much lower than that usually seen in PBMC from adult individuals [25,26].

Fig. 3.

Fig. 3

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Frequencies of IFN-γ-producing cells/100 000 CBMC in response to allergens, PHA or PPD from children with different atopic heredity. ▪, dh = double heredity (n = 20), Inline graphic, mh = maternal heredity (n = 18), □, nh = no heredity (n = 19). Frequencies were measured in ELISpot in triplicate, spontaneous production subtracted and mean values ±s.e.m. are shown.

IL-4/IFN-γ ratios and correlations

Interindividual variations in the numbers of IFN-γ- as well as IL-4-producing cells after PHA stimulation were large. Interestingly, individuals could be divided into high, intermediate or low producers, as reflected by a significant correlation between the number of IL-4 and IFN-γ-producing cells (Fig. 4, r = 0·72, P <0·0001). To overcome the problem with interindividual variation, we have reported previously that calculating the ratio between Th2/Th1-type of responses might be more appropriate [27]. In agreement with this, we demonstrate here that when estimating the individual IL-4/IFN-γ ratios in response to PHA, there was a significant Th2 bias in the dh group compared to the nh group (P < 0·05, Fig. 5). There was a tendency for a positive correlation between CB IgE levels and the IL-4/IFN-γ ratios in the dh group (r = 0·45 P = 0·056) which, however, was not seen in the other groups (not listed).

Fig. 4.

Fig. 4

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Correlation between IL-4 and IFN-γ-producing cells/100 000 cells in response to PHA in CBMC from children with different atopic heredity (n = 56). Correlation coefficient, r = 0·72, P < 0·0001. Frequencies were measured in ELISpot in triplicate and spontaneous production was subtracted.

Fig. 5.

Fig. 5

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Ratios between IL-4 and IFN-γ-producing cells/100 000 cells in response to PHA in CBMC from children with different atopic heredity. ▪, dh = double heredity (n = 20), Inline graphic, mh = maternal heredity (n = 17), □, nh = no heredity (n = 19). Frequencies were measured in ELISpot in triplicate, spontaneous production subtracted, individual ratios were calculated and mean ratios ±s.e.m. are shown.

IL-12-producing cells in CBMC

The mean spontaneous production of IL-12 was 4·4 ± 7·6 spots/100 000 cells (no differences between the groups). Following allergen stimulation, a large number of cells produced IL-12. The group without atopic heredity exhibited significantly higher numbers of IL-12-producing cells compared to the group with only maternal heredity, which again displayed the lowest number of cytokine-producing cells (P < 0·01 for birch and cat allergens, Fig. 6). The dh group showed an intermediate number of IL-12-producing cells in response to all allergens. The T cell mitogen PHA induced very few IL-12-producing cells (10·3 ± 8·9; 4·7 ± 12·8; 8·0 ± 8·5 for the dh, mh and nh groups, respectively). Similarly, following PPD stimulation the mean numbers were low: 8·3 ± 9·7; 13·0 ± 19·8; 21·9 ± 35·0 in the dh, mh and nh groups, respectively.

Fig. 6.

Fig. 6

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Frequencies of IL-2-producing cells/100 000 CBMC in response to birch, ovalbumin or cat allergens, PHA or PPD from children with different atopic heredity. ▪, dh = double heredity (n = 20), Inline graphic, mh = maternal heredity (n = 18), □, nh = no heredity (n = 19). Frequencies were measured in ELISpot in triplicate, spontaneous production subtracted and mean ratios ±s.e.m. are shown.

DISCUSSION

It has been suggested that an atopic mother has a stronger influence on the atopy development of a child than an atopic father. Thus, the fetal environment might be of importance for allergy predisposition. In this study we evaluated the influence of maternal atopic heredity on in vitro activated allergen-specific or non-specific cytokine-producing CBMC. Our study groups included mh – maternal atopic heredity, nh – no atopic heredity, and dh – a group with double atopic heredity. The latter group was enrolled to assess possible additional contribution from the father. In line with data published by others [1–3], allergen-specific cytokine responses by CBMC from children both with and without atopic mothers could be detected, suggesting that allergen priming occurs in utero independent of the atopic status of the mother.

CB IgE levels have been evaluated in several studies as a predictor for atopic disorders in childhood. However, the predictive value of CB IgE has been questioned [28,29]. The present study did not reveal any differences in CB serum IgE levels between the groups with or without atopic heredity. However, a correlation between CB IgE and maternal IgE in the two groups with atopic mothers (dh and mh) was seen, suggesting a maternal influence on the CB IgE levels, and is in agreement with studies published by others [30]. When relating the CB IgE to the ratio of IL-4/IFN-γ-producing CBMC after PHA stimulation, a tendency for a positive correlation could be seen in the dh group. This indicates that the IgE is indeed produced by fetal cells, also shown by Sverremark et al. [31].

The T cell mitogen PHA induced high numbers of IL-4- and IFN-γ-producing cells. Somewhat surprising, the mh group displayed significantly lower frequencies of both IL-4- and IFN-γ-producing cells compared to the dh group. In addition, for IFN-γ, there was also a significant difference to the nh group. The reasons for this are unknown, but might in part be due to a large interindividual variation. To overcome this problem with variation, the ratio of IL-4-/IFN-γ-producing cells following PHA stimulation was used to estimate the Th2/Th1 balance. The most prominent Th2 bias was found in the dh group, and a significant difference could be seen to the nh group, the latter having the lowest Th2/Th1 ratio. Hence, our data indicate a strong genetic influence on the cytokine pattern in CBMC, where an atopic father has at least as much influence as the mother. Since our initial hypothesis concerned solely the influence of maternal atopy, a group with only atopic fathers was not included in the study.

We also stimulated CBMC with the allergens birch, ovalbumin and cat. While low numbers of IL-4-producing cells could be detected, IFN-γ-producing cells were induced in response to allergens in all three groups. A tendency for lower numbers of IFN-γ-producing cells in the dh group was observed, which is in line with what has been described earlier, e.g. by Prescott et al., who showed reduced IFN-γ production in CBMC from individuals who later developed atopy [16]. However, we show a significant induction of IFN-γ after allergen stimulation in all three groups, whereas Prescott et al. detected IFN-γ only in the group who did not develop atopy at 2 years of age. Compared to in vitro allergen-induced IFN-γ responses by adult PBMC [32], the production by CBMC was lower. This could be due to lack of surface molecules required for the generation of Th1 responses. Baldini et al. have shown recently that a mutation in the CD14 gene influences both the serum levels of total IgE and T cell responses [33]. In line with this, we found high numbers of IFN-γ-producing cells following PHA stimulation, suggesting that the low allergen-induced IFN-γ is due to a defect at the APC level. This is also in agreement with what has been published by others [34].

An interesting finding was that high numbers of IL-12-producing cells were induced in response to allergen in all three groups. However, the number of IL-12-producing cells was significantly lower in CBMC from children in the mh group compared to the nh group, which suggests a reduced Th1 induction in these individuals. This difference could be due to skewed distributions of functionally distinct DC subsets [35,36]. Despite the relatively high numbers of IL-12-producing cells in all three groups, we observed low numbers of IFN-γ-producing cells in response to allergens. This indicates a low responsiveness to IL-12, which could be explained by an absence or low expression of the signalling (β2) subunit of the IL-12 receptor (IL-12R) on T cells [37,38], or by genetic variations in the IL-12Rβ2 [39].

The numbers of IL-12-producing cells in CBMC after stimulation with PHA were significantly lower than those seen after activation with allergen, and also lower than those usually seen in adult PBMC (A. Söderlund, unpublished results). IL-12 is produced following the interaction of CD154 expressed on T cells and CD40 on APCs. Several reports have described a defective up-regulation of CD154 on CB T cells after stimulation which does not engage the T cell receptor [40–42], whereas the induction of CD154 expression was normal after anti-CD3 stimulation [40]. Thus, a possible explanation for the low numbers of IL-12-producing cells following PHA stimulation could be a defective up-regulation of CD154 on CB T cells. To elucidate this we are presently investigating the CD154 expression on CB T cells before and after activation.

In conclusion, our results suggest a skewing towards Th2 responses in neonates, which is most obvious after mitogen stimulation of CBMC from individuals with double atopic heredity. A novel finding in this study was that large numbers of IL-12-producing cells were induced following allergen stimulation. Despite this, low numbers of allergen-specific IFN-γ-producing cells were seen. Thus, our results are in line with the current dogma of neonatal immunity, claiming a defective Th1 cytokine production in cord blood. How our results relate to the actual development of allergy in these children is presently under investigation.

Acknowledgments

This work was supported by The King Gustaf V 80-years Jubilee Foundation, The Swedish Asthma and Allergy Association, the Swedish Society for Medical Research and the Vårdal Foundation. We thank Ann Sjölund and Anna-Stina Ander for excellent technical assistance. We are also grateful to all the families who provided blood samples for this study.

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