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* Clinical Chemistry and Molecular Diagnostics,
Department of Internal Medicine-Cardiology, Hospital of Philipps University, Marburg, Germany;
Charité, Campus Virchow-Clinic, Berlin, Germany; and
Deutsches Rheumaforschungszentrum, Berlin, Germany
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Abstract |
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production. Development of an IgE response against the same allergen was completely prevented early in life. This effect was mediated by diaplacental transfer of allergen-specific IgG1 Abs. In contrast, allergic sensitization against a different allergen early in life was accelerated in these mice. This effect was mediated by maternal CD4 and OVA-specific Th2 cells induced by allergic sensitization during pregnancy. These data indicate a critical role for maternal T and B cell response in shaping pre- and postnatal maturation of specific immunity to allergens. |
Introduction |
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production is markedly reduced compared with later in life (4, 6, 7). However, an even further reduced capacity to secret Th1 cytokines has been related to the risk and development of allergies, particularly in the first few years of life. These and other data recently resulted in the concept that an impaired level of Th1 immunity may favor the development of allergies. Further indirect evidence for this hypothesis comes from epidemiological studies performed in rural areas of infants living on farms, where prenatal contact to the farming environment conveys protection against respiratory allergies (8, 9, 10). This effect has been related to high levels of endotoxins, particularly those present in stables and farm houses (2). Furthermore, a recent intervention study revealed that prenatal administration of certain lactobacilli that are known as potent Th1/Th2 modifiers, markedly reduced the development of atopic eczema in early childhood (11). Maternal adaptive immunity has a strong influence on the immune responses of the offspring. This phenomenon has probably been best studied in diaplacental and breast milk transmission of Abs. Not only do these Abs provide passive protection against infections, but they might also actively shape childhood immunity and tolerance induction by providing the fetus and the infant with the mother’s immunological experience (12). In this regard, the diaplacental transfer of IgG Abs and the presence of high amounts of secretory IgA Abs in breast milk might play an important role (13). However, whether the T cell compartment might also be actively involved in regulating pre- and postnatal immunity has not been extensively studied to date. It was the purpose of this project to examine whether and how the maternal Ag experience during pregnancy affects the development of the allergen-specific Th2 immune response in early life. It was of particular interest to examine the impact of the maternal T and B cell system in this regard. The experiments were conducted in a well-established murine model of experimental allergy that was adapted to the situation of prenatal inhalant allergen exposure (14).
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Materials and Methods |
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Female BALB/c mice were sensitized by repeated i.p. injections of 10 µg of chicken OVA (grade VI; Sigma Chemie, Deisenhofen, Germany) emulsified in 1.5 mg of Al(OH)3 (Inject Alum; Pierce, Rockford, IL) on days -21, -7, and -1 before mating. During the gestation period mice were exposed to OVA-aerosol (1% OVA diluted in PBS) every second day as previously described (15). Age-matched control animals received sham injections (i.p.) of PBS and were exposed to PBS-aerosol. In certain experiments offspring received a single (i.p.) injection of 10 µg of 
-lactoglobulin (BLG2; Sigma Chemie) emulsified in 1.5 mg of Al(OH)3 at 4 wk of age. The experiments were approved by the Regierungspräsidium Giessen.
Determination of allergen transfer to the fetus
Pregnant BALB/c mice received a single i.v. injection of 10, 20, or 40 mg of OVA on day 19 of pregnancy. After 6 h, serum from BALB/c mothers, fetal serum, and amniotic fluid were collected. Isoelectric focusing of serum and amniotic fluid was performed in polyacrylamide gels (pH 4.0–6.5) using the PhastSystem (Amersham Pharmacia Biotech, Freiburg, Germany), followed by immunofixation as described previously (16). Immunofixation was performed by incubation with either polyclonal anti-mouse IgG serum (anti-OVA serum) or nonimmune mouse serum (control serum). Nonprecipitated (non-OVA) proteins were removed by washing the gels with 150 mmol/liter NaCl for 40 h with vigorous agitation. Immunofixed proteins were silver-stained in the PhastSystem Development Unit as described previously (17).
Determination of allergen-specific IgE, IgG1, and IgG2a Ab titers
Allergen-specific IgE, IgG1, and IgG2a Ab titers were measured by ELISA as previously described (15). The anti-OVA IgE/IgG1/IgG2a and anti-BLG IgG1/IgG2a Ab titers of the samples were related to the concentration of an anti-OVA-specific IgG1 mAb (Sigma Chemie) or to a pooled standard serum that was generated in the laboratory.
Assessment of immediate cutaneous hypersensitivity reactions
Intracutaneous skin testing was performed as previously described (15).
Determination IFN-
IFN- was measured in culture supernatants by ELISA as previously described. The sensitivity was 50 pg/ml (15).
Flow cytometric analysis of cell surface markers and intracellular cytokine production
The distribution of T cell subpopulations was analyzed by flow cytometry (FACS). The following FITC-labeled mAbs were used: rat anti-mouse CD3 (clone 145-2C11), CD4 (clone H129.19), CD8 (clone 53-6.7), CD19 (clone 1D3), and Thy-1 (clone HO-13; BD PharMingen, Hamburg, Germany). To analyze intracellular cytokine expression, cells were fixed in formaldehyde (2% diluted in PBS) and suspended in saponin (0.5% diluted in PBS/0.5% BSA). The frequencies of IL-4 and IFN- (rat 
-IL-4, clone 11B11; rat -IL-5, clone TRFK5; rat -IFN-, clone XMG1.2) producing T cells were determined after stimulation with PMA (10 ng/ml) and ionomycin (1 µg/ml) for 6 h at 37°C in the presence of monesin to block intracellular protein transport as previously described (18). Background, determined by blocking of specific binding, was <0.5%.
Determination of IFN--producing MNC by the ELISPOT technique
Ninety-six-well plates were coated with anti-IFN- mAb (clone R4-6A2; BD Biosciences, Heidelberg, Germany) at a concentration of 5 µg/ml. After 24 h wells were blocked by incubation with 3% BSA/PBS for 2 h. Either 5 x 104 or 10 x 104 MNC/well were added and stimulated by PMA (10 ng/ml) and ionomycin (1 µg/ml) for 48 h at 37°C in 5% CO2. After washing with PBS containing 0.1% Tween 20, secondary Ab was added (biotin-conjugated anti-IFN-, clone XMG-1.2; BD Biosciences) at a concentration of 2 µg/ml for 24 h, followed by incubation with 5-bromo-4-chloro-3-indolyl-phosphat (Calbiochem, Bad Soden, Germany), and was developed with nitro blue tetrazoliumchloride (Calbiochem). Spots were counted under the microscope.
Transfer of CD4-positive T cells from OVA-sensitized BALB/c mice to pregnant SCID mice and postnatal challenge of the offspring with BLG or OVA
Splenic mononuclear cells (MNC) from OVA-sensitized BALB/c were prepared by density centrifugation. CD4-positive cells were purified by the MACS technique. The remaining cells contained 
90% CD4-positive cells as determined by FACS analysis. Cells were washed with PBS, and SCID mice were passively reconstituted by i.v. injection of 2 x 107 cells and 50 µg OVA on days 2 and 10 of pregnancy (CD4). Controls (-/-) received 50 µg OVA only. All F1 offspring received a single injection of OVA or BLG 28 days after delivery. Thirty-five days after the injection, anti-BLG IgG1 and anti-OVA IgG1 titers were determined.
Transfer of OVA-specific Th2 cells from OVA-TCR transgenic mice
Single-cell suspensions were prepared from spleens of OVA-TCR transgenic BALB/c mice. Cells were suspended in RPMI 1640/10% FCS culture medium (Biochrom, Berlin, Germany). MNC were purified by density gradient centrifugation (Lympholyte M; Cedarline Laboratories, Hornby, Canada; 1000 x g, 20 min, room temperature), washed twice (800 x g, 10 min, room temperature), and suspended in culture medium. Cells were stimulated for 4 days in the presence of anti-CD3, anti-IFN-, and IL-4 as described previously (19). The portion of Th1 or Th2 cells was determined by assessment of intracellular cytokine expression by flow cytometry as described above. The frequency of IL-4-positive cells was >40%, and that of IFN--positive cells was <1%. OVA-Th2 cells (2.5 x 106) were injected together with 50 µg of OVA into naive BALB/c mice on day 2 of pregnancy. Controls received OVA alone.
Transfer of anti-OVA IgG1 mAbs to pregnant SCID mice
SCID dams received 0.2 mg of monoclonal anti-OVA IgG1 (Sigma Chemie) i.v. plus 50 µg of OVA i.v. on days 2 and 10 of pregnancy and 4 days after delivery of their offspring. Controls received OVA alone. All (SCID x BALB/c)F1 received a single injection of OVA or BLG 28 days after delivery. Thirty-five days after the injection anti-BLG IgG1 and anti-OVA IgE titers were determined.
Statistical analysis
Results are presented as the mean ± SEM. Student’s t test was used to determine the level of difference between animal groups.
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Results |
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BALB/c mice were immunized to OVA and exposed during pregnancy to OVA-aerosol. Pre- and postnatal maternal transfer of allergen-specific Igs was assessed in (BALB/cOVA x BALB/c)F1 at birth and followed up for to 60 days. Among IgG subclasses, different patterns of Ab transfer were observed. At birth, the anti-OVA IgG1 Abs were present in the offspring, but at a lower concentration than in maternal blood. During breastfeeding the IgG1 Ab titer further increased in a linear fashion and extended the maternal levels. This was most likely due to colostral-intestinal absorption. After weaning, IgG1 Ab titers decreased, with a half-time of 
7 days. Because of the anaphylactogenic properties of these Abs, it was not surprising that all offspring from OVA-sensitized mothers responded with positive immediate-type cutaneous hypersensitivity to OVA (Table I). A different pattern of diaplacental/trans-intestinal transfer was observed for anti-OVA IgG2a Abs. Anti-OVA IgG2a Abs were present at birth, but Ab titers were higher than those in maternal blood. Starting from birth, anti-OVA IgG2a Ab titers declined, with a half-time of 7 days, indicating an exclusive diaplacental transfer of IgG2a Abs. In contrast, there was no detectable pre- or postnatal transfer of Igs of the IgE isotype (Fig. 1).
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To assess whether allergen can cross the maternal-fetal barrier, normal mice received a single bolus injection of OVA on day 19 of pregnancy. Maternal and fetal blood and amniotic fluid were prepared 6 h later. Matched samples were separated by isoelectric focusing, and OVA was detected by immunofixation with an anti-OVA-specific antiserum. As shown in Fig. 2, free OVA was detected in maternal and fetal blood as well in the amniotic fluid. Mice that did not receive OVA served as controls. This result provides direct evidence that allergen can cross the decidual-placental interface.
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production in (BALB/c x BALB/c)F1 from OVA-sensitized BALB/c mice
To assess the effect of maternal immunization on the development of fetal Th1 responses, mice were immunized during pregnancy in a fashion that induced a Th2 response. Splenic MNC were prepared at birth, and the frequencies of IFN--producing cells as well as levels of IFN- production were assessed by ELISPOT and ELISA, respectively (Fig. 3, A and B). After stimulation of splenic MNC with PMA/ionomycin, a lower frequency of IFN--producing cells was detected in (BALB/cOVA x BALB/c)F1. In addition, the level of IFN- production was significantly reduced in (BALB/cOVA x BALB/c)F1 compared with offspring from nonsensitized mothers. The average production of IFN- per cell did not significantly differ between the study groups (p > 0.05). These data indicate that the reduction in IFN- was due to a lower frequency of IFN--producing cells, and the production of IFN- per cell was not significantly altered.
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production, the experiments were repeated with female SCID mice (SCIDOVA) mated to BALB/c wild-type males. Offspring were fully immunocompetent. In the absence of a functional maternal adaptive immune system, both the frequency and the total amount of IFN- production were lower at birth than in offspring from immunocompetent mothers. However, maternal immunization did not further reduce neonatal IFN- production (Fig. 3, A and B).
It was then examined whether maternal allergen-specific Th2 cells regulate the reduced IFN- production. Therefore, in vitro-generated, OVA-specific Th2 cells were injected together with OVA into pregnant mice on day 3 postconception (BALB/cTh2-OVA). MNC were prepared at birth, and the frequencies of IFN--producing cells as well as the levels of IFN- production were assessed. In the presence of Th2 cells during pregnancy, splenic MNC from offspring showed both lower frequency and lower total amount of IFN- at birth compared with controls (Fig. 4, A and B). These results indicate that a portion of fetal/neonatal IFN- production is regulated by the maternal Th2-type cells. In addition, offspring from BALB/cTh2-OVA mothers developed more rapidly, as indicated by a significantly (p < 0.05) higher body weight at 15 days of age compared with wild-type animals. In contrast, pregnancy was aborted by the injection of in vitro-generated, OVA-specific Th1 cells on day 3 postconception. These results support recent observations in humans suggesting that a Th2-biased cytokine profile favors the success of pregnancy and that increased Th1 cytokine expression may be the underlying mechanism for reproductive failure.
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Since IFN- production has been identified as a major inhibitor for the development of Th2 immunity, we tested the hypothesis that reduced Th1 responsiveness at birth accelerates and/or augments the development of Th2 responses later in life. For this purpose mice received a single i.p. injection of OVA or a novel allergen (BLG) to which the mother had never been exposed on day 28 postpartum. The development of anti-OVA and anti-BLG Ig production was followed at weekly intervals. Before immunization, no anti-OVA IgE or anti-BLG IgG1 Abs were detectable in the sera of these mice (Fig. 5, A and B). Although normal mice mounted a strong anti-OVA IgE response after OVA immunization, this response was absent in (BALB/cOVA x BALB/c)F1 mice (Fig. 5A). An opposite pattern of allergen-specific Ig production was observed after exposure to the novel allergen. After BLG immunization, the levels of anti-BLG IgG1 Ab titers were significantly higher in offspring from mothers that were sensitized to OVA (BALB/cOVA x BALB/c)F1 (Fig. 5B). These results indicate that the type and level of allergen-specific Ig production are differentially regulated depending on maternal immune status during pregnancy.
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It was then examined whether these effects depend on maternal CD4+ cells or Igs. To assess the role of CD4+ T cells, SCIDOVA mice mated with BALB/c wild-type mice were reconstituted with CD4+ T cells from OVA-sensitized mice on days 2 and 10 of pregnancy. Offspring were challenged either with OVA or the novel allergen (BLG) as described above. The immune responses to both Ags were augmented in offspring from CD4OVA mothers compared with offspring from controls (Fig. 6).
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In the next experiment the effect of diaplacentally transferred Abs on the development of postnatal immune responses was assessed. Female SCID mice were mated with wild-type BALB/c males (SCID x BALB/c). On days 2 and 10 of pregnancy and 3 days after birth, the Ab response to OVA was passively reconstituted by i.v. injection of monoclonal anti-OVA-IgG1. At 28 days of age, -OVA IgG1 Abs were detected at a concentration of 4.2 ± 0.8 µg/ml serum into (SCID x BALB/c)F1 mice. These offspring were immunized with OVA or BLG (Fig. 7). Assessment of Ab responses revealed complete suppression of anti-OVA IgE production compared with untreated mice, which responded normally (Fig. 7). In contrast, the Ab response to BLG, the novel Ag, was not affected by the presence of anti-OVA IgG1 (Fig. 7).
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To examine whether the above-described effects persist into (early) adulthood of mice, offspring were immunized with either OVA or BLG at 3 mo of age. Pilot experiments revealed that maternally derived anti-OVA IgG1 Abs were undetectable at this age (data not shown). Mice were immunized with a single OVA injection, and Ab titers were monitored 56 days later. Regardless of whether the offspring were derived from sensitized or nonsensitized mothers, similar titers of anti-OVA IgE and anti-OVA IgG1 Ab were detected in both groups (Table II). However, when the mothers received Ag-specific Th2 cells, an augmentation of both IgE and IgG1 Abs was detectable at this age. This augmenting effect was also detectable when mice were sensitized to BLG (Table II). These data indicate that the immunosuppressive effect mediated by IgG1 Abs disappeared with the disappearance of these maternally derived Abs, and conversely, the augmenting effect provided by (maternal) Th2 cells still persisted up to 3 mo of age.
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Discussion |
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The murine model shows striking similarities to the human situation in several respects. At birth, human and murine neonates show a markedly reduced level of IFN- production. In our model neonatal IFN- production was even further suppressed if the mother showed a Th2-biased immune response induced by allergic sensitization during pregnancy. This further suppression was the result of a lowered frequency of IFN--secreting cells. However, the average level of IFN- production per cell remained the same, pointing toward regulatory elements that act possibly during pregnancy and/or early childhood. Neonatal T cells are intrinsically capable of reaching an adult level of function, but only if an apparent increased requirement for costimulatory signals is provided (20, 21, 22). It was then examined whether this phenomenon will account for the observation of an augmented and accelerated allergic immune response against the novel allergen BLG. However, at the time of sensitization to BLG, IFN- production reached levels comparable to those observed in control mice, making it unlikely that the diminished IFN- response at birth is directly responsible for the observed effects. However, IFN- deficiency in neonates may be attributed to the decreased activity of neonatal dendritic cells. It was shown that the response of cord blood dendritic cells to LPS is consistently abrogated, with almost complete failure to produce IL-12p70 (23).
Another important feature of our murine model is allergen transfer across the placental barrier. Recently, using an in vitro perfusion model, allergen transfer across the human placenta has been described. In this model, transfer could be increased in the presence of human IgG Abs, suggesting active uptake of Ag via the formation of immune complexes (24). In another study house dust mite allergen has been detected in maternal blood as well as in matched samples of amniotic fluid (25). In addition, Ag-specific responses may be induced by other means, such as anti-idiotypic Abs (26, 27). The passage of free Ag or Ag in the form of immunocomplexes provides the basis for the development of fetal Ag-specific T cell responses. In humans, mature CD4 or CD8 single-positive T cells are readily detectable by wk 17 of gestation (28). Therefore, Ags presented during the third trimester of pregnancy are capable of inducing an Ag-specific T cell response in utero. In the mouse, mature T cells are detectable toward the end of pregnancy (around day 19). Therefore, the development of Ag-specific T and B cell responses in the offspring may occur only in very late pregnancy or must occur after birth when rapid expansion of the T and B cell pool takes place.
Maternal transfer of Igs represents a prime candidate for Ag-specific immunomodulation. Therefore, we have carefully analyzed the patterns of Igs before and after birth. Comparable to the human immune system, IgE Abs were neither pre- nor postnatally transmitted. In contrast, different patterns of Ab transfer have been observed for various IgG classes. Whereas IgG2a Abs are only transmitted prenatally, the transfer of IgG1 Abs occurs pre- and postnatally. Even more strikingly, maternal IgG1 Ab titers further increase in a linear fashion during breastfeeding, suggesting an active mechanism of uptake. It has been shown that the MHC class I-like receptor FcRn plays an important role in this mechanism. This receptor is expressed in gut epithelial cells of murine neonates and recently has been also found in human gut epithelial cells. Our data provide evidence that suppression of humoral immune responses in the neonates were mediated through these maternally derived IgG Abs. This effect is Ag specific and completely protects the formation of an IgE response in the offspring. The ability of IgG Abs to inhibit the induction of humoral immune responses is a well-known phenomenon (29, 30). In a recent study Victor et al. (31) developed a similar model of prenatal sensitization, followed by postnatal Ag challenge. Their model allergen is the house dust mite allergen, Der p. Rechallenge of young mice with Der p inhibited IgE and IgG1 responses, and the inhibitory effect decreased with aging. The authors report that these observations mainly depend on the level of maternal Abs. In the present study we have now formally proven the relevance and dependency of maternal Abs for postnatal immunosuppression to a homologous allergen. Ag exposure causes cross-aggregation between IgG1 Abs bound to these FcRIIs and surface Ig expression by the B cell receptor. This cross-aggregation induces a state of negative intracellular signals that prevents these cells from switching toward IgE and subsequently to IgE production.
This mechanism has been used in clinical trials in which Ab treatment prevents a graft-vs-host reaction of the fetus against the mother. In the case of rhesus factor incompatibility treatment, this anti-rhesus Ab during pregnancy also avoids a graft-vs-host reaction of the fetus against the mother (32, 33). In the case of allergy there are several observations indirectly supporting this concept of Ab-mediated tolerance induction. The success of specific immunotherapy has been related at least in part to the presence of so-called blocking Abs of the IgG isotype. Furthermore, children from allergic women receiving grass pollen immunotherapy during pregnancy were protected from the development of immediate hypersensitivity reactions to the same allergen (34). More recently, epidemiological studies indicate that the presence of high titers of cat-specific IgG Abs is inversely related to the risk of developing cat allergies (35). Along this line, increased levels of maternal anti-Bet v 1 Abs at birth have been associated with a reduced prevalence of allergies at 18 mo of age (36).
During the development of an allergic immune response, the production of allergen-specific IgG1 Abs is under close control of Th2 cells. We have used an immunization and challenge protocol that induced such a Th2 T cell response during pregnancy. When these offspring were sensitized to a different Ag, in our case BLG, CD4-positive Th2 cells promote the development of an allergic immune response in the offspring. In terms of Ab titers against BLG, the immune responses were augmented and accelerated compared with controls. Victor et al. (31) also found in their model an augmented immune response to a heterologous allergen (in their case OVA) administered on day 35. This effect disappeared at older ages, indicating a transient phenomenon. Our model provides evidence that maternal CD4 T cells account for this effect. Maternal CD4 Th2 cells may act via different pathways in this context. Maternally derived T cells have been previously detected in the fetal/neonatal circulation. It might also be possible that cytokines, including IL-4, IL-13, and others derived from these T cells, may pass the placental barrier and provide a local cytokine milieu that favors the development of Th2 immune responses. Further studies are currently in progress to delineate the underlying mechanism of this effect.
As a control in our T cell transfer experiment we used Th1 T cells that were administered in the same way as the Th2 cells. To our surprise, the transfer of such Th1 cells resulted in almost complete intrauterine resorption. These data further support the concept that the maternal Th1/Th2 milieu is important for fetal survival and successful pregnancy. To prevent fetal loss it seems to be necessary to provide a local environment at the fetal-maternal interface that is dominated by Th2 and Th3 immune responses (37). Any changes in favor of the Th1-dominated immune pattern results in a negative outcome of pregnancy (38, 39). This might provide one explanation why Th1 immunity, as reflected by the production of IFN-, is so extremely low in the neonates and even lower in neonates derived from allergic mothers.
In conclusion, we have developed a model to assess the impact of the maternal B and T cell compartments on the development of allergic immune responses in early life. Maternally transmitted IgG1 Abs play an important role in the development of Ag-specific tolerance in the offspring. In contrast, an opposite effect has been observed for Th2 T cells, which augment and accelerate allergic immune responses in an Ag-independent fashion. One of the major challenges in the future will be the development of appropriate prevention strategies for allergy and asthma. Based on our and other data it seems to be important to introduce any kind of preventive measure early in life, perhaps even before birth.
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Footnotes |
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2 Abbreviations used in this paper: BLG, -lactoglobulin; MNC, mononuclear cell.
Received for publication January 29, 2003. Accepted for publication July 23, 2003.
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References |
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secretion in neonates and subsequent atopy. Lancet 344:1516.
and in interleukin-4-expressing cells. Eur. J. Immunol. 24:1097.[Medline]
on interferon- producing T cells from mouse and man. Eur. J. Immunol. 26:263.[Medline]
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