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Background: During pregnancy, variations in maternal–foetal cellular interactions may influence immune programming. This study was carried out to determine if maternal responses to foetal alloantigens are altered by maternal allergic disease and/or previous pregnancies.
Methods: For this cohort study, peripheral blood was collected from allergic (n = 69) and nonallergic (n = 63) pregnant women at 20, 30, 36-week gestation and 6-week postpartum (pp). Cord blood was collected at delivery. Mixed lymphocyte reactions were used to measure maternal cytokine responses [interleukin-6 (IL-6), IL-10, IL-13 and (interferon-γ) IFN-γ] at each time point towards foetal mononuclear cells.
Results: Maternal cytokine responses during pregnancy (20, 30 and 36 weeks) were suppressed compared to the responses at 6-week pp. The ratio of maternal IFN-γ/IL-13 and IFN-γ/IL-10 responses were lower during pregnancy. Allergic mothers had lower IFN-γ responses at each time-point during pregnancy with the greatest difference in responses observed at 36-week gestation. When allergic and nonallergic women were further stratified by gravidity group, IFN-γ responses of allergic multigravid mothers were significantly lower than nonallergic multigravid mothers during pregnancy.
Conclusions: During normal pregnancy, peripheral T-cell cytokine responses to foetal alloantigens may be altered by both allergic status of the mother and previous pregnancies. These factors could influence the cytokine milieu experienced by the foetus and will be further explored in the development of allergic disease during early life.
Patterns of perinatal immune responses have been convincingly linked to the risk of subsequent allergic disease. The most consistent of these observations has been that the ‘normal’ T-helper cell type 1 (Th-1) immaturity of the neonatal period is more profound in newborns with allergic predisposition (1–5). This has generated enormous interest in the potential factors that could influence early immune function and predisposition to disease. An increasing number of studies have examined the effects of environmental influences during pregnancy and demonstrated that exogenous factors, such as microbial exposure (6), maternal diet (7, 8) and smoking (9) can have effects on developing immune responses. However, endogenous influences such as variations in cellular interactions at the maternal–foetal interface have not been extensively studied.
Immune interactions between mother and foetus play an important role in determining cytokine homeostasis during pregnancy. Successful pregnancy involves a relative Th-2 cytokine bias in the placenta, which occurs under the influence of hormonal changes (10–12). This is reflected by foetal responses at birth which are also relatively ‘Th-2 skewed’ (4), indicating that this shift in cytokine expression has a critical effect on subsequent immune development.
Direct interaction between mother and foetus has the capacity to influence the pattern of foetal immune development by subtle alterations of immune responses during pregnancy. A recent exploratory study by our group showed that maternal responses to foetal alloantigen were directly related to foetal Th-2 [interleukin-13 (IL-13), IL-10] cytokine responses and allergic outcomes at 6 years of age (13). Here, we explore the hypothesis that allergic mothers, who have a predisposition towards Th-2-like responses to allergens, also produce such a response to foetal alloantigen during pregnancy, modifying the Th-1/Th-2 polarity during pregnancy. Maternal atopy has been reported to have a stronger effect than paternal allergy on allergy risk (14, 15) as well as Th-1 immune dysfunction in newborns that later developed allergic symptoms (16). These observations support a direct gestational influence of maternal allergy on immune development. In this study, we examine how maternal allergic status influences maternal responses to foetal alloantigens.
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Many factors during pregnancy, both maternal and environmental, may play a role in the development of the immune system. The cellular interaction between mother and foetus could be the most direct influence on foetal immune responses. To our knowledge, this is the first study to measure maternal peripheral responses to the foetus over the course of pregnancy and in the context of allergic disease.
In this study, maternal cytokine responses during pregnancy were suppressed compared to the nonpregnant state. Consideration of the effect of lactational status on the pp responses was also of concern as some research has observed increased cytokine production of both Th-1 and Th-2 cytokines from lymphocytes of breastfeeding mother in ex vivo cultures compared to formula feeders and controls (17–19). However, in this study cytokine responses were still higher pp after adjusting for breastfeeding status. Alternatively, the suppression of maternal alloantigen responses during pregnancy could be caused by actions of pregnancy hormones such as progesterone (20) and/or development of maternal tolerance specifically to paternal alloantigen (21). There is general agreement that the placental interface is not completely impermeable during human pregnancy as there is evidence for two way cell trafficking across this barrier (22, 23) and antibodies directed towards paternal HLA expressed on foetal cells are commonly detected in the peripheral blood of pregnant women. This indicates that maternal immune cells are likely to encounter and respond to foetal antigens throughout the course of pregnancy, highlighting the importance of these mechanisms in preventing foetal immune rejection.
Regulatory T cells (TReg) including the naturally occurring CD4+ CD25+ TReg cells expand during normal human pregnancy (24). The consequences of a deficient activity of TReg cells, namely immunological spontaneous abortion, has been demonstrated in a murine model (25) suggesting these cells may be important for preventing maternal immune rejection. The cytokine IL-10 is produced by some TReg subsets, however, our results did not show an increase in maternal IL-10 responses during pregnancy, rather they were significantly dampened compared to the nonpregnant state. In other studies, IL-10 levels were not upregulated in abortion-prone mice who received TReg cells from normal pregnant mice (26), and IL-4/IL-10 knockout in mice resulted in normal pregnancies (27). Therefore, IL-10 may not be crucial in pregnancy for promoting maternal tolerance to paternal alloantigens. Instead TReg cells may promote maternal–foetal tolerance by activating alternative pathways, such as production of other immunosuppressive molecules i.e. TGF-β (28, 29).
There are a number of factors which may have influenced the alloimmune responses observed in this study. Previous studies have suggested that maternal allergy can affect T-cell responses during pregnancy as circulating IFN-γ and IL-13 producing T lymphocytes were increased in asthmatic pregnant women (30). The tendency for allergic mothers in this study to have higher IL-13 but reduced IFN-γ responses to their foetus could consequentially lead to a gestational environment where there is potentially reduced signals for foetal Th-1 maturation that may contribute to atopic risk of the infant (13). Birth order has also been reported to influence allergy risk with studies showing negative associations between sib-ship size and allergic manifestations (reviewed in 31). It is still not known, however, whether the reduced risk of children born into larger families is because of more frequent exposure to pathogens during early childhood or to increasing parity influencing the maternal interaction with her offspring (32). If birth order does play an important role in allergy risk, it would be expected that subsequent pregnancies might lead to lower Th-2 and/or increased Th-1 type responses to the foetus. However, the results of this study are not consistent with the birth order effect. Whether a lack of difference is caused by sample size, or requires study of other Th-2 cytokines such as IL-4 or IL-5 is not certain. Unexpectedly, multigravid mothers with allergic disease showed the lowest IFN-γ responses compared to nonallergic mothers and both allergic and nonallergic primigravids. It is possible that the maternal Th-1 immune response to alloantigen may be less aggressive in this particular subset of women. Further follow-up study of the infants born to these women is required to determine if these subtle interactions between allergic and gravidity status of the mother have any clinical significance after birth. Human leukocyte antigen mismatch between mother and foetus is also likely to account for some of the variations in immune responses in this study (13) and HLA compatibility may also explain why there was a subset of mothers who showed nondetectable cytokine responses. This laboratory will be typing mothers and infants for future studies to confirm these speculations.
In conclusion, during normal pregnancy, peripheral T-cell cytokine responses to foetal alloantigens may be altered by both allergic status of the mother and previous pregnancies. Follow-up studies of the infants are underway to determine the role of these responses in the development of allergic disease.