Maternal allergen immunisation to prevent sensitisation in offspring: Th2-polarising adjuvants are more efficient than a Th1-polarising adjuvant in mice

Background

Preconception allergen immunization prevents neonatal allergen sensitization in mice by a complex interaction between regulatory cells/factors and antibodies. The present study assessed the influence of maternal immunization with ovalbumin (OVA) on the immune response of 3 day-old and 3 week-old offspring immunized or non-immunized with OVA and evaluated the effect of IgG treatment during fetal development or neonatal period.

Results

Maternal immunization with OVA showed increased levels of FcγRIIb expression in splenic B cells of neonates, which were maintained for up to 3 weeks and not affected by additional postnatal OVA immunization. Maternal immunization also exerted a down-modulatory effect on both IL-4 and IFN-γ-secreting T cells and IL-4 and IL-12- secreting B cells. Furthermore, immunized neonates from immunized mothers showed a marked inhibition of antigen-specifc IgE Ab production and lowered Th2/Th1 cytokine levels, whereas displaying enhanced FcγRIIb expression on B cells. These offspring also showed reduced antigen-specific proliferative response and lowered B cell responsiveness. Moreover, in vitro evaluation revealed an impairment of B cell activation upon engagement of B cell antigen receptor by IgG from OVA-immunized mice. Finally, in vivo IgG transference during pregnancy or breastfeeding revealed that maternal Ab transference was able to increase regulatory cytokines, such as IL-10, in the prenatal stage; yet only the postnatal treatment prevented neonatal sensitization. None of the IgG treatments induced immunological changes in the offspring, as it was observed for those from OVA-immunized mothers.

Conclusion

Maternal immunization upregulates the inhibitory FcγRIIb expression on offspring B cells, avoiding skewed Th2 response and development of allergy. These findings contribute to the advancement of prophylactic strategies to prevent allergic diseases in early life.     

Maternal allergen immunization during pregnancy in a mouse model reduces adult allergy-related antibody responses in the offspring

BACKGROUND: The immune status and allergen exposure of the mother may influence the immune response in the offspring after birth. This relationship may be important both for allergen avoidance strategies and, alternatively, for allergy prophylaxis by allergen exposure of the mother. OBJECTIVE: The aim of the present study was to investigate the effect of allergen immunization of the mother during pregnancy and postpartum, in relation to the allergy-related immune response (IgE) and the non-allergy-related (IgG2a) response in the offspring. METHODS: Pregnant NIH/OlaHsd females were immunized three times during pregnancy and one time postpartum with ovalbumin and the adjuvant Al(OH)3, and the offspring's ovalbumin-specific IgE, IgG1 and IgG2a responses were measured after challenge with the same allergen as young adults. Ovalbumin-specific IgE, IgG1 and IgG2a responses were also analysed in offspring of NIH/OlaHsd females immunized once at different times during pregnancy: about 3 days into pregnancy, mid-pregnancy (10 days into pregnancy) and about 4 days before giving birth (17 days into pregnancy). RESULTS: Allergen immunization of mother during pregnancy and postpartum significantly reduced the IgE response in the progenies, whereas the IgG2a response to the same allergen was increased. Allergen immunization of the mother 3 days into pregnancy resulted in a significantly lower IgE response in offspring compared with the response in offspring of non-immunized mothers and in offspring of mothers immunized 17 days into pregnancy. CONCLUSIONS: Maternal allergen immunization might favour selection for an allergen-specific Th1-dependent antibody response in the offspring. Our results indicate that IgE suppression is stronger after maternal allergen exposure during early pregnancy than after exposure in late pregnancy.     

Allergic sensitization and allergen exposure during pregnancy favor the development of atopy in the neonate

BACKGROUND: Several studies have considered that the in utero environment plays an important role in the onset of the allergic phenotype. We assessed whether allergic sensitization and allergen exposure during pregnancy favor the postnatal onset of allergy in the neonate. METHODS: BALB/c mice were sensitized to ovalbumin (OVA) before mating followed by allergen aerosol exposure during pregnancy. T and B cell responses in offspring were followed up until day 60 postpartum. At the age of 4 weeks offspring were exposed to a heterologous antigen, beta-lactoglobulin (BLG). RESULTS: Pregnant mice developed immediate hypersensitivity responses and Th-2/ Th-0 immunity following allergen aerosol exposure. At birth, T cells from offspring of nonsensitized BALB/c mice were characterized by an impaired IFN-gamma production, which was lowered even further in offspring of OVA-sensitized BALB/c mice. Offspring of OVA-sensitized BALB/c mice responded with immediate-type cutaneous hypersensitivity reactions to OVA which could be related to the pre- and postnatal transfer of maternal OVA-specific IgG1 antibodies. After exposure to BLG, offspring of OVA-sensitized BALB/c mice developed an accelerated Th-2-driven immune response compared to offspring from nonsensitized BALB/c mice as indicated by enhanced anti-BLG IgG1 antibody production and increased numbers of positive immediate-type cutaneous hypersensitivity reactions to BLG. CONCLUSION: Our data suggest that Th-2/Th-0 immunity present during pregnancy has a decisive impact on shaping the Th-1/Th-2 T cell profile in response to postnatal allergen exposure.     

Impact of in utero Th2 immunity on T cell deviation and subsequent immediate-type hypersensitivity in the neonate

It was the aim of this study to analyze the impact of maternal Th2 immune responses on onset and subsequent development of allergen-specific immunity and immediate-type hypersensitivity in early childhood. In a well characterized mouse model of Th2 immunity, BALB / c mice were sensitized to ovalbumin (OVA) before mating followed by allergen aerosol exposure during pregnancy. At the end of pregnancy mice developed allergen-specific Th2 / Th0 immunity and immediate-type hypersensitivity responses to OVA. T cells from these newborns, when restimulated with PMA / ionomycin, demonstrated a lowered capacity to produce IFN-gamma. To assess whether prenatal allergen exposure favors postnatal onset of a Th2-type immune response, these offspring were immunized to a novel antigen by a single injection of beta-lactoglobulin (BLG). In contrast to offspring from non-sensitized mothers, offspring from OVA-sensitized mice showed both higher anti-BLG immunoglobulin titers and higher frequencies of immediate-type skin test responses. Our data suggest that Th2 / Th0 immunity present during pregnancy has a decisive impact on shaping of the Th1 / Th2 T cell profile in the neonate. Furthermore, this effect favors the development of Th2 immune responses, when mice are exposed to a novel antigen during early childhood.     

Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: development of tolerance using environmental antigens

BACKGROUND: Studies show that children in rural environments develop less asthma and allergic rhinitis than their urban counterparts. This may be a result, in part, of neonatal exposure to environmental antigens such as LPS and/or early exposure to allergens. OBJECTIVE: This study examined the effects of neonatal allergen and/or LPS exposure on subsequent immune responses to allergen. METHODS: Newborn mice were exposed to LPS and/or ovalbumin. At age 6 weeks, these animals were sensitized and challenged with ovalbumin, and airway inflammation, hyperresponsiveness, and cytokine expression were assessed. RESULTS: Animals exposed to LPS in the neonatal period developed T cells expressing CD25 and IL-10 on sensitization and challenge. They demonstrated abrogation of airway hyperresponsiveness and significant decreases in IL-13 from bronchoalveolar lavage fluid and in specific IgE. IL-4-expressing spleen cells were also significantly decreased. Mice exposed in the neonatal period to ovalbumin demonstrated airway hyporesponsiveness after subsequent ovalbumin sensitization and challenge and did not produce specific IgE. In contrast, these animals showed increases in IFN-gamma. Animals exposed to both LPS and ovalbumin developed a response characterized by IL-10 and IFN-gamma-expressing T cells. CONCLUSION: This suggests that mucosal antigen exposure in the neonatal period results in inhibition of allergic responses to environmental allergens. Early LPS exposure directs mucosal responses toward tolerance, whereas ovalbumin exposure follows the T(H)1-type response on subsequent sensitization. CLINICAL IMPLICATIONS: This study suggests that prevention of airways allergy may be best achieved by appropriate exposure of the airway mucosa early in life to environmental antigens.     

Prenatal lipopolysaccharide-exposure prevents allergic sensitization and airway inflammation, but not airway responsiveness in a murine model of experimental asthma

BACKGROUND: Epidemiological evidence underlines the impact of prenatal environmental factors on the development of postnatal allergies. In this regard an inverse correlation between lipopolysaccharide (LPS) exposure and development of childhood allergy has been found. OBJECTIVE: To assess the impact of prenatal LPS exposure on the development of postnatal respiratory allergies in a mouse model of experimental asthma. METHODS: Female BALB/c mice were exposed to LPS before conception and during pregnancy. Several weeks after birth offspring were sensitized to ovalbumin (OVA) followed by aerosol allergen challenges. RESULTS: Prenatal, maternal LPS-exposure enhanced neonatal IFN-gamma, but not IL-4 and IL-2 production. OVA sensitization of prenatally LPS-exposed mice was accompanied by a marked suppression in anti-OVA IgG1 and IgE as well as unchanged IgG2a antibody responses, paralleled by a significant reduction in IL-5 and IL-13 levels following mitogenic stimulation of splenic leucocytes. Assessment of bronchoalveolar lavage fluids following allergen challenges revealed a marked reduction in eosinophils and macrophages in these mice. Surprisingly, development of airway hyper-responsiveness, a hallmark of bronchial asthma, was not affected. CONCLUSION: This study provides first experimental evidence that LPS may already operate in prenatal life in order to modulate the development of allergies in the offspring.     

Preconception maternal immunization to dust mite inhibits the type I hypersensitivity response of offspring

BACKGROUND: The maternal immunologic experience associated with early life exposure to allergens might contribute to the development of allergy during infancy. OBJECTIVES: We sought to analyze the effect of the mother's immunization before conception with the dust mite Dermatophagoides pteronyssinus on the allergen priming and hypersensitivity response in early immunized offspring. The kinetics of D pteronyssinus immunization were observed from newborn to adult age, and the secondary response to D pteronyssinus was followed in offspring immunized in early life. METHODS: Female A/Sn mice were immunized or not with D pteronyssinus and mated with male C57BL/6 mice. The hybrid offspring were immunized to investigate allotypes and subclasses of anti-D pteronyssinus antibody, as well as total IgE levels, by using ELISA and anti-D pteronyssinus IgE antibody by using the passive cutaneous anaphylaxis reaction. Ovalbumin was used for heterologous immunization. Cytokines were measured in the cell-culture supernatant by means of ELISA, and CD4(+)CD25(+) cells were analyzed by means of flow cytometry. RESULTS: Offspring from immune mothers have not shown evidence of prenatal or postnatal allergen priming with respect to humoral level. Immunization with D pteronyssinus of offspring at very early life and in the postweaning period inhibited anti-D pteronyssinus IgE and IgG1 antibody production, along with the expected presence of maternal antibody. Furthermore, offspring antibody responsiveness from immune mothers has remained quiescent on secondary allergenic challenge. This maternal influence on the offspring antibody response was specific to D pteronyssinus because the immunization with a heterologous antigen did not alter IgE response. Maternal D pteronyssinus immunization induced a significant decrease of the IFN-gamma level in the offspring, avoided an exacerbation of T(H)2 cytokine secretion, and, concomitantly, upregulated the number of CD4(+)CD25(+) T cells. CONCLUSION: Maternal immunization to D pteronyssinus seems to protect offspring from the development of allergy.     

Maternal respiratory sensitization and gestational allergen exposure does not affect subsequent pup responses to homologous or heterologous allergen

Evidence suggests that the predisposition towards atopy begins early in life. Maternal allergy has been associated with an increased risk of the development of allergic disease in offspring. Some studies suggest that the development of childhood atopy may also be influenced by prenatal allergen exposure. In this study, a respiratory allergen exposure model was used to determine the impact of maternal sensitization (with or without additional exposures during pregnancy) on subsequent pup responses to homologous or heterologous allergen. Female BALB/c mice received two intratracheal aspiration (IA) exposures to Metarhizium anisopliae crude antigen (MACA) or Hank’s buffered salt solution (HBSS) prior to breeding. Some mice also received three additional exposures during pregnancy. Control mothers did not receive treatment. Young adult offspring received three IA exposures to MACA, house dust mite extract (HDM) or HBSS. Offspring sensitized as young adults to either HDM or MACA developed an airway inflammatory response, including increased bronchoalveolar lavage fluid lactate dehydrogenase activity, total protein and total and differential cell counts compared to offspring exposed to HBSS. Increased airway responsiveness to methacholine was observed in pups treated with HDM but not with MACA. Maternal sensitization status (with or without gestational allergen exposure) had no effect on offspring response to either MACA or HDM. In conclusion, this study demonstrates that IA administration of MACA or HDM extract to young adult BALB/c mice induces the development of an inflammatory airway response. In contrast to previous reports, neither maternal sensitization nor gestational allergen exposure could be demonstrated to have a clear effect on offspring sensitization. This discrepancy may be a function of the respiratory sensitization and exposure protocol used in this study, which mimics natural sensitization more closely than do parenteral routes of exposure.     

Influence of maternal murine immunization with Dermatophagoides pteronyssinus extract on the type I hypersensitivity response in offspring

BACKGROUND: Maternal exposure to environmental ubiquitous allergens could exert an influence on the newborn's immune repertoire and the later development of allergy. The aim of this study was to investigate the effects of maternal immunization with Dermatophagoides pteronyssinus (Dp) on the hypersensitivity response and IgG subclass production in offspring using a murine model. METHODS: A/Sn mice were immunized with Dp before mating with normal A/Sn males. Diaplacental serum samples were collected from newborn mice delivered by cesarean section, and maternal milk samples were extracted from the stomachs of newborn mice. Groups of offspring 25 or 45 days old were Dp immunized and boosted on the 10th day after sensitization. The animals were bled 7 days after the booster. RESULTS: High levels of anti-Dp IgG subclasses - mainly IgG1, but also IgG2a and IgG2b - were transmitted by immunized mice via the placenta to the offspring. In the milk from immunized mothers, significant levels of anti-Dp IgG subclasses and anti-Dp IgM and IgA antibodies were detected. Moreover, the increase in total IgA antibodies in the milk of the immunized females correlated with a significantly increased level of TGF-beta1. TGF-beta2 levels were markedly higher than the beta1 isoform in the milk, although no difference was observed between the groups. When offspring from immunized mothers were sensitized at 25 days, a significant decrease in total and anti-Dp IgE antibodies as well as total and anti-Dp IgG1, IgG2a and IgG2b subclasses was observed compared to normal female offspring, whereas when offspring were sensitized at 45 days, both offspring groups showed similar levels of IgE and IgG subclasses. CONCLUSIONS: Our study showed that maternal immunization with Dp promotes the transference of specific antibodies and/or TGF-beta, which can negatively modulate the allergic response in offspring, and suggests that maternal preexposure to allergen before mating can protect mice during the early phase.     

Maternal tolerance achieved during pregnancy is transferred to the offspring via breast milk and persistently protects the offspring from allergic asthma

Background Maternal, more than paternal, asthma is a risk factor for the development of asthma in children. Recently, epidemiologic studies have shown that environmental exposures during pregnancy might influence the development of childhood asthma and allergies. Objective The aim of the present study was to investigate whether the induction of tolerance against a specific antigen during pregnancy prevents in the offspring the development of allergic asthma in response to this antigen. Methods Balb/c mice were orally tolerized with ovalbumin (OVA) during pregnancy. The offspring of tolerized and naïve mothers were immunized with OVA at 6 weeks and 4 months of age and analysed in our murine asthma model. Results While the offspring of naïve mice developed increased AHR, eosinophilic airway inflammation, T‐helper type 2 cytokine production and high serum IgE levels in response to OVA sensitization, the offspring of tolerized mice were almost completely protected from asthma, even when immunized as late as 4 months after birth. Breastfeeding was crucial for protection because tolerance was only observed when the offspring were nursed by their own mothers and not when nursed by naïve wet‐nurses. Allergen‐specific IgG₁ antibodies were exclusively increased in the breast milk of tolerant mothers and serum of protected pups, indirectly supporting its important role in tolerance transfer from the mother to the offspring. Sensitization of the F1 generation from OVA‐tolerized mothers with a heterologous allergen enhanced the immune response to this antigen. Conclusion Our results demonstrate that mucosal allergen contact during pregnancy modifies the asthma and allergy risk of the offspring mediated via breast milk. This observation may suggest that the time window for primary prevention strategies starts even before early childhood during pregnancy.     

Exposure to high doses of birch pollen during pregnancy,and risk of sensitization and atopic disease in the child

BACKGROUND: The role of maternal allergen exposure during pregnancy in sensitization and development of atopic disease in the child remains controversial. In the spring of 1993, extremely high levels of birch pollen were recorded in Stockholm, Sweden. In 1994, the corresponding pollen levels were low. The aim of this study was to assess the influence of exposure during pregnancy to high/low doses of birch pollen on the risk of sensitization and development of atopic disease in children. In addition, a comparison was made with children exposed to birch pollen in early infancy. METHODS: Three hundred and eighty-seven children with atopic heredity, born in Stockholm in July-October 1993 or 1994 (mothers exposed during pregnancy), were investigated at age 4.5 years. The children were clinically examined and were skin prick tested (SPT) with inhalant and food allergens. IgE antibodies (RAST) against birch pollen and recombinant birch pollen allergen (rBet v 1) were analysed in serum. A comparison was made with a similar group of children exposed during the same incident, but in the first 3 months of life, in 1993. RESULTS: The children of mothers high-dose exposed during pregnancy in 1993 tended to be more sensitized (SPT > or = 3 mm) to birch pollen than the children with low-dose exposure during the corresponding period in 1994 (7.6 and 4.6%, respectively, OR: 1.7; 95% CI: 0.7-4.1). A similar but weak tendency was seen for positive RAST analyses (> or =0.35 kU/l) against birch pollen and rBet v 1. Children of mothers high-dose exposed during pregnancy were significantly less sensitized to birch pollen than the children high-dose exposed in early infancy (17.9%, OR: 0.4; 95% CI: 0.2-0.7). There was an overall trend towards a slightly increased prevalence of bronchial asthma, allergic rhinoconjunctivitis and atopic dermatitis in the group with mothers high-dose exposed during pregnancy, compared to those with low exposure. CONCLUSION: Exposure of the mother during pregnancy to high levels of birch pollen resulted in a tendency towards increased risk of sensitization to the same allergen and symptoms of atopic disease in children with atopic heredity. Furthermore, our data indicate that exposure of the mother during pregnancy to inhalant allergens is less likely to result in sensitization in the child than exposure of the child in early infancy.     

Perinatal Immunization With Vaccine-Grade Listeria monocytogenes Provides Protection Against Murine Th2 Airway Inflammation

Purpose

Asthma is a chronic respiratory disorder that leads to inflammation and narrowing of the airways. Its global prevalence has attained epidemic levels and treatment options that reach beyond temporary relief of symptoms are urgently needed. Since the processes leading to clinically symptomatic asthma start early in life, we set out to systematically evaluate a neonatal immunotherapeutic based on Listeria monocytogenes (Lm) for the control of allergic sensitization.

Methods

We modified Lm to express the model allergen, ovalbumin (OVA), and tested the ability of neonatal immunization with this strain to control allergic sensitization in a mouse model of OVA-induced asthma. Mice were immunized as newborns with live or heat killed LmOVA or live Lm, followed 6 weeks later by allergic sensitization with OVA. In order to determine whether the T_H1-polarizing effect of this vaccine vector inadvertently may exacerbate development of certain T_H1-driven allergic diseases, mice immunized as newborns were assessed in a model of adult hypersensitivity pneumonitis (HP).

Results

Both LmOVA and Lm-control vaccines were highly effective in providing long-lasting protection from airway inflammation after only one immunization given perinatally. Serum antibody levels and lung cytokine production suggest that this prophylactic strategy is associated with an allergen specific T_H1-dominated response. Specifically, LmOVA vaccinated mice displayed significantly elevated OVA-specific serum IgG2a, but no difference in anti-OVA IgE antibodies and only slightly decreased anti-OVA IgG1 antibodies. Importantly, Lm-based neonatal vaccination did not exacerbate Th1/Th17 driven HP, arguing against broad spectrum immune skewing.

Conclusions

Our findings highlight the promise of early life Lm-based immunomodulatory interventions as a prophylactic strategy for allergic asthma.     

Maternal and newborn immunization with a human immunodeficiency virus-1 immunogen in a rodent model

We examined immunization with an inactivated, gp120-depleted human immunodeficiency virus (HIV) antigen in incomplete Freund's adjuvant (IFA), also containing a sequence of immunostimulatory (ISS) DNA, during the last trimester of pregnancy and neonatally in a rat model. Pregnant rats were immunized in the third trimester and their litters were immunized during the newborn period. In addition, litters of rats from non-immunized mothers were immunized during the neonatal period. As another control, pregnant rats were immunized and their litters analysed. Supernants from peripheral blood mononuclear cells (PBMCs) were assayed from newborns at 4 weeks of age for HIV-specific interferon-gamma (IFN-gamma), HIV-specific regulated on activation, normal, T-cell expressed, and secreted (RANTES), and serum for p24 antigen-specific immunoglobulin G (IgG) production. In the animals whose pregnant mothers were immunized and were also immunized during the neonatal period, we observed HIV-specific IFN-gamma production and HIV-specific RANTES production, but weak p24 IgG antibody production. Animals immunized only during the neonatal period developed the highest levels of HIV-specific IFN-gamma production, but somewhat lower levels of HIV-specific RANTES and p24 IgG antibody production. The group of animals whose mothers had received immunizations during the last trimester of pregnancy, but were not immunized during the neonatal period, developed the strongest p24 IgG antibody levels, but little or undetectable HIV-specific IFN-gamma or RANTES production. Neonatal immunization resulted primarily in cell-mediated immune responses, while animals born to mothers who were immunized during the last trimester had primarily an antibody-mediated immune response. Immunization of pregnant animals followed by neonatal immunization resulted in a mixed cell-mediated/antibody type profile in the neonatal animal. Future studies should provide insights into neonatal immunity and potential vaccine approaches to prevent neonatal infection and perinatal transmission.     

Endotoxins and allergy: lessons from the murine model.

Exposure early in life to organic dusts containing immunomodulatory components such as endotoxins and immunizing components such as aeroallergens may greatly influence whether subsequent encounters with allergens lead rather to sensitization or unresponsiveness. We investigated the effects of endotoxin in the context of allergen-mediated immune responses in a murine model of allergen sensitization. Systemic sensitization with ovalbumin induced high serum levels of allergen-specific IgE, predominant Th2-type cytokine production, eosinophilic airway inflammation and in vivo airway hyperreactivity. Endotoxins were either applied systemically prior to sensitization, or via the airways prior to airway challenges, or by repeated inhalation during the first weeks of life prior to subsequent sensitization. Different effects of endotoxins on allergen-induced immune responses may be attributed to differences in dosing, route of application, time relationship with allergen sensitization and the concurrent exposure to endotoxin and allergen. The results of these studies may help to define the effects of endotoxin on allergen-mediated immune reactions and to further delineate the important interrelationships between environment and disease development. Finally, this may lead to new strategies in the prevention and treatment of allergic diseases.     

Allergen exposure in infancy and the development of sensitization, wheeze, and asthma at 4 years

BACKGROUND: The relationship between mite and pet allergen exposure in infancy and the subsequent development of sensitization and asthma is complex. OBJECTIVE: We prospectively investigated the effect of allergen exposure at 3 months of age on the development of sensitization, wheeze, and physician-diagnosed asthma in the first 4 years of life in a birth cohort of children with and without an atopic mother. METHODS: Children participated in the Prevention and Incidence of Asthma and Mite Allergy study. Allergen exposure at 3 months of age was determined from mattress dust samples. Specific IgE to inhalant allergens was measured at 4 years of age, and information about wheeze and physician-diagnosed asthma was collected with yearly questionnaires. RESULTS: Mite and cat allergen exposure in infancy were associated with an increased risk of specific sensitization to house dust mite and cat, respectively, at 4 years of age. There were borderline significant associations between cat allergen exposure and persistent wheeze in the total study population and between dog allergen exposure and persistent wheeze in children with a nonatopic mother. In children with an atopic mother, there was some indication of a positive association between mite allergen exposure and physician-diagnosed asthma. CONCLUSION: Early house dust mite and cat allergen exposure might lead to sensitization and, in case of cat allergen exposure, to persistent wheeze. Early mite and dog allergen exposure might lead to asthma and persistent wheeze, respectively, but only in subgroups defined by maternal atopy.     

Neonatal interleukin-12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods

BACKGROUND AND OBJECTIVES: A reduced capacity of antigen presenting cells (APC) to provide pro-T helper 1 (Th1) signals, such as IL-12, to T cells during early life may be implicated in the development of T helper 2 (Th2)-mediated allergic disease. In this study we examined the relationships between the capacity for IL-12 responses in the neonatal period and atopic risk (family allergy), in vitro T cell responses to allergens, and the subsequent development of allergic disease at 6 years. METHODS: The capacity of circulating neonatal (and maternal) APC to produce IL-12 p70 in response to LPS (and IFN-gamma) stimulation was assessed in a group of 60 children with previously well-characterized immune responses to allergens and atopic outcomes. The IL-12 responses were compared with allergen-induced lymphoproliferation (to house dust mite (HDM) ovalbumin (OVA), cat and beta-lactoglobulin (BLG)) and IL-13 and IFN-gamma cytokine responses (to OVA, HDM and phytohaemaglutinin (PHA)) in the neonatal and postnatal periods. IL-12 responses were also compared according to atopic risk and atopic outcomes (doctor-diagnosed asthma, eczema, food allergies and sensitization as evidenced by skin prick testing) at 6 years clinical follow-up. RESULTS: Maternal peripheral blood mononuclear cells (PBMC) synthesized significantly greater amounts of IL-12 than neonatal PBMC, though within maternal-infant pairs IL-12 responses were significantly correlated (r = 0.4, P = 0.019). Moreover, neonatal IL-12 responses were positively correlated with neonatal allergen proliferation for HDM (r = 0.6, P < 0.0001), OVA (r = 0.55, P < 0.0001), cat (r = 0.5, P = 0.003) and BLG (r = 0.55, P = 0.001), but negatively correlated with neonatal IL-13 responses to both allergens tested (HDM: r = - 0.4, P = 0.03 and OVA: r = - 0.5, P = 0.001). Both neonatal and maternal IL-12 responses were positively correlated with postnatal IFN-gamma responses to HDM at 12, 18 and 24 months of age (responses after age of 2 years were not assessed). There was no relationship between atopic risk and IL-12 capacity in the neonatal period, but there was a (non-significant) trend for neonatal IL-12 responses to be lower in the high-risk children who developed clinical allergy at 6 years (compared with the low risk group) although the number in this analysis was small. CONCLUSIONS: Reduced APC IL-12 production in the perinatal period was associated with reduced T cell activation (lymphoproliferation), stronger neonatal Th2 responses, and weaker Th1 responses to allergen in the postnatal period. This supports the notion that variations in APC function in early life may contribute to altered allergen-specific cytokine responses associated with later allergy.     

Effect of age and maternal antibodies on the systemic and mucosal immune response after neonatal immunization in a porcine model

Newborn mammals are highly susceptible to respiratory infections. Although maternal antibodies (MatAb) offer them some protection, they may also interfere with their systemic immune response to vaccination. However, the impact of MatAb on the neonatal mucosal immune response remains incompletely described. This study was performed to determine the effect of ovalbumin (OVA) ‐specific MatAb on the anti‐OVA antibody response in sera, nasal secretions and saliva from specific pathogen‐free Vietnamese miniature piglets immunized at 7 or 14 days of age. Our results demonstrated that MatAb increased antigen‐specific IgA and IgG responses in sera, and transiently enhanced an early secretory IgA response in nasal secretions of piglets immunized at 7 days of age. In contrast, we detected a lower mucosal (nasal secretion and saliva) anti‐OVA IgG response in piglets with MatAb immunized at 14 days of age, compared with piglets with no MatAb, suggesting a modulatory effect of antigen‐specific maternal factors on the isotype transfer to the mucosal immune exclusion system. In our porcine model, we demonstrated that passive maternal immunity positively modulated the systemic and nasal immune responses of animals immunized early in life. Our results, therefore, open the possibility of inducing systemic and respiratory mucosal immunity in the presence of MatAb through early vaccination.     

Serum ovalbumin-specific immunoglobulin G responses during pregnancy reflect maternal intake of dietary egg and relate to the development of allergy in early infancy

BACKGROUND: The value of allergen elimination diets during pregnancy for primary prevention of infant allergy has been questioned. However, dietary compliance may influence effectiveness. OBJECTIVES: To monitor egg intake during a randomized controlled trial of egg avoidance throughout pregnancy and lactation by serial measurements of serum ovalbumin (OVA) IgG concentration in conjunction with dietary diary record and also, to analyse specific IgG concentrations at birth in relation to infant allergic outcome. METHODS: Pregnant women, with personal or partner atopy, were randomized to complete dietary egg exclusion or an unmodified healthy diet before 20 weeks gestation. The infants were evaluated for atopy at 6 months of age. Serum food-specific IgG concentrations were determined by ELISA in maternal samples collected at study recruitment and during labour, and in infant samples at birth (umbilical cord). RESULTS: Serum-specific IgG to OVA, but not the unrelated allergen, cow's milk beta-lactoglobulin, decreased over pregnancy in egg-avoiding women only (P<0.001). Cord OVA IgG concentration correlated with maternal IgG at delivery (r=0.944; P<0.001), and for infants born to atopic women, cord concentration was higher than that of their mother's (P<0.001). Infants with the lowest and highest cord IgG concentrations were the least likely, and those with mid-range concentrations were the most likely, to be atopic by 6 months of age (P=0.008). CONCLUSION: Serum OVA IgG concentration reflects egg consumption, thereby indicating dietary allergen doses to which the developing immune system might be exposed. Trans-placental maternal IgG must be considered among early life factors that regulate infant atopic programming.     

Primary sensitization in infants.

OBJECTIVE: It has become increasingly clear that the mechanisms by which an allergic immune response is generated are complex and may begin even before a baby is born. Genetic, environmental, nutritional, and immunologic factors acting during pregnancy all play a role in determining whether or not a baby is born with a propensity to develop allergic sensitization and subsequent allergic disease. The objective of the research described in this article is to determine whether manipulation of any or all of these could lead to prevention of disease. DATA SOURCES: The database used was Medline up to and including 1997. The Conference Proceedings of the XVth World Congress of Asthmology in Montpellier 1996 are quoted. Many of the research hypotheses are generated from work performed in our own laboratories. STUDY SELECTION: The criteria used to select studies for review centered around a necessity for the data to have been collected in very early life with, if possible, a follow-up period to determine disease progression, or for the data to have been collected during pregnancy to elucidate primary mechanisms. RESULTS: It has been shown that a fetus is able to mount a proliferative response to a common allergic trigger (beta-lactoglobulin, house dust mite, etc) as early as 22 weeks of pregnancy. Maternal exposure to allergens influences her own IgG production which modulates the allergen exposure of the fetus resulting in either primary sensitization of T cells or "tolerance" to the allergen. Atopic mothers create a more Th2-orientated environment for the developing fetus than non-atopic mothers. CONCLUSIONS: Manipulation of the maternal immune response during pregnancy, either by altering her environment or controlling her allergic reactions, may be a method of preventing the development of allergic disease in infants.     

The effects of pregnancy on the exacerbation and development of maternal allergic respiratory disease

The T-helper 2 (T_H2) bias associated with pregnancy may predispose the pregnant mother to the development or exacerbation of allergic disease. To determine the effects of pregnancy on pre-existing maternal sensitization, we sensitized BALB/c mice before breeding by two intratracheal aspiration (IA) exposures to the fungal allergen, Metarhizium anisopliae crude antigen (MACA). Some mice also received three IA exposures to MACA on gestational days 11, 15, and 19. After weaning, all mice were challenged IA with MACA before killing. To determine the effects of pregnancy on susceptibility to future sensitization, naïve parous and nulliparous BALB/c mice were sensitized by three IA exposures to MACA or to Hank’s buffered salt solution vehicle control. Pregnancy did not have a significant effect on individual inflammatory parameters (airway responsiveness to methacholine, total serum and bronchoalveolar lavage fluid (BALF) IgE, BALF total protein, lactate dehydrogenase activity, and total and differential cell counts) following allergen challenge in sensitized mice, regardless of post-breeding allergen exposure. In conclusion there was a weak inhibition of the overall response in mice exposed to allergen during pregnancy compared to identically treated nulliparous mice. In contrast, parous mice that did not encounter allergen post-breeding tended to have exacerbated responses. Parity had no significant impact on future susceptibility to sensitization.