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BackgroundPreconception 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.ResultsMaternal 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.ConclusionMaternal 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.

Summary Allergen exclusion measures during pregnancy and lactation have been given consideration in studies of primary allergy prevention but complete avoidance of mother/neonatal allergen exposure has proven to be a difficult procedure. To evaluate a strategy to prevent allergen sensitization in early life in mice, we first established a neonatal model with ovalbumin sensitization through maternal allergen exposure during pregnancy or breastfeeding. The modulatory potential of preconception immunization was investigated on the neonatal development of subsequent allergic responses to maternal allergen exposure. Herein, we demonstrate that immunized mothers exposed to antigen during pregnancy or breastfeeding underwent intense vertical transmission of antibodies, including immunoglobulin G (IgG) in complex with ovalbumin and IgG1 antibody with anaphylactic function. It was further shown that maternal immunization efficiently decreased the passage of free antigens through breastfeeding and inhibited the enhanced IgE antibody response after postnatal antigen exposure. In addition, antenatal immunization decreased the antigen‐specific proliferative response of immunized neonates, in parallel with profound downmodulatory effects on both the activation and differentiation of T and B cells after a non‐specific stimulus and cytokine production. These findings showed that early life sensitization, subsequent to maternal allergen exposure during both the prenatal and postnatal periods, could be avoided by preventive vaccination of the mother.

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-β1. TGF-β2 levels were markedly higher than the β1 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-β, 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.

Balance between early life tolerance and sensitization in allergy: dependence on the timing and intensity of prenatal and postnatal allergen exposure of the mother Introduction Early childhood is a phase of life with a high risk of allergic sensitization -it is the time when initial allergen sensitization frequently occurs.1,2 The immature status of the immune system in early life, 3,4 and the predisposition towards T helper type 2 (Th2) skewing of immune function during fetal and neonatal periods 5,6 may collectively contribute to the initial development of an allergic response subsequent to allergen exposure. Maternal allergen exposure seems to be a risk factor for early atopic disorders, influenced by genetic and environmental factors. 7,8 Therefore, it is important to understand the relationship between the amount and timing of initial allergen exposure as a factor in the early development of sensitization.Maternally derived dietary allergen exposure has been associated with the presence of the allergen in fetal circulation, implying that the fetus may be exposed to dietary allergen during pregnancy transplacentally or SummaryAllergens can be maternally transferred to the fetus or neonate, though it is uncertain how this initial allergen exposure may impact the development of allergy responses. To evaluate the roles of timing and level of maternal allergen exposure in the early life sensitization of progeny, female BALB/c mice were given ovalbumin (OVA) orally during pregnancy, lactation or weekly at each stage to investigate the immunoglobulin E (IgE) antibody production and cellular responsiveness of their offspring. Exposure to OVA during pregnancy was also evaluated in OVA-specific T-cell receptor (TCR) transgenic (DO11.10) mice. The effect of prenatal antigen exposure on offspring sensitization was dependent on antigen intake, with low-dose OVA inducing tolerance followed by neonatal immunization that was sustained even when pups were immunized when 3 weeks old. These offspring received high levels of transforming growth factor-b via breastfeeding. High-dose exposure during the first week of pregnancy or perinatal period induced transient inhibition of IgE production following neonatal immunization; although for later immunization IgE production was enhanced in these offspring. Postnatal maternal antigen exposure provided OVA transference via breastfeeding, which consequently induced increased offspring susceptibility to IgE antibody production according to week post-birth. The effect of low-dose maternal exposure during pregnancy was further evaluated using OVA transgenic TCR dams as a model. These progeny presented pronounced entry of CD4 + T cells into the S phase of the cell cycle with a skewed T helper type 2 response early in life, revealing the occurrence of allergen priming in utero. The balance between tolerance and sensitization depended on the amount and timing of maternal allergen intake during pregnancy.Keywords: breastfeeding; immunoglobulin E antibodies; in utero priming; maternal allerg...

The innate and adaptive immune responses in neonates are usually functionally impaired when compared with their adult counterparts. The qualitative and quantitative differences in the neonatal immune response put them at risk for the development of bacterial and viral infections, resulting in increased mortality. Newborns often exhibit decreased production of Th1-polarizing cytokines and are biased toward Th2-type responses. Studies aimed at understanding the plasticity of the immune response in the neonatal and early infant periods or that seek to improve neonatal innate immune function with adjuvants or special formulations are crucial for preventing the infectious disease burden in this susceptible group. Considerable studies focused on identifying potential immunomodulatory therapies have been performed in murine models. This article highlights the strategies used in the emerging field of immunomodulation in bacterial and viral pathogens, focusing on preclinical studies carried out in animal models with particular emphasis on neonatal-specific immune deficits.

We investigated the effect on specific antibody response of naive and sensitized mice orally administrated with low (0.25 mg) or high (10.0 mg) doses of Dermatophagoides pteronyssinus (Dp) extract. We also examined the effect of oral administration of Dp on the production of autoantibodies to immunoglobulin G (IgG) and immunoglobulin E (IgE). Naive and sensitized mice both showed a marked down-regulation of IgE antibody production, regardless of the dose of Dp. We also detected an inhibitory effect of the total IgE levels and the allergen-specific IgG1, IgG2a and IgG2b antibody response in sensitized mice given the low dose of Dp. In contrast, high doses of Dp stimulated IgG1 antibody production in both naive and sensitized animals. In addition, the oral tolerance induction protocol stimulated anti-F(ab')2gamma and anti-Fcgamma autoantibody production. Evaluation of IgG anti-IgE autoantibodies by a direct enzyme immunoassay (EIA) revealed the presence of these autoantibodies, predominantly of the IgG1 isotype, specifically in those animals fed with the high dose. In contrast, IgG-IgE complexes, determined by EIA using immobilized anti-IgE antibodies, were detected mainly in sera of control animals. The autoantibody anti-IgE specificity was tested against IgE-TNP and IgE-DANSYL murine proteins and revealed different inhibition profiles, suggesting the action of heterogeneous subpopulations of autoantibodies. Taken together, our results show that the oral tolerance protocol with Dp was able to modulate the production of allergen-specific IgE antibodies in both naive and sensitized animals. In addition, we suggest that anti-IgE autoantibodies participate in the modulation of allergic response triggered by oral tolerance protocols.

SUMMARYOne of the main goals of immunotherapy of allergic diseases is the down-regulation of the type I hypersensitivity reaction. We investigated in this study the effect of oral administration of varying doses (0·25, 1·0, 4·0 and 10 mg) of dust mite extract (Dermatophagoides pteronyssinus, Dp) in sensitized A/Sn mice. A marked decrease of the allergen-specific immunoglobulin E (IgE) response was observed with all antigen doses. The mice orally tolerized with low Dp dose (0·25 mg) had a significant decrease in the total serum IgE and in the immunoglobulin G1 (IgG1), IgG2a and IgG2b antibody levels. The higher Dp dose (10·0 mg), however, enhanced the IgG1 antibody response, suggesting the stimulation of a pre-existing immune response of the sensitized animals. Animals fed with the low Dp dose had a significant decrease in the frequency of interleukin-4 (IL-4) secreting cells. These animals also showed a significant decrease in the frequency of Dp-specific IgE-and IgG1-positive plasma cells. Our data suggest that feeding dust mite extract to Dp-sensitized mice down-regulates the development of type I hypersensitivity, by inhibition of the T helper 2 response. INTRODUCTIONit is unclear how and whether these oral tolerance-induced IL-4-producing cells can modulate allergic responses that are In allergic processes, cytokines secreted by T helper 2 (Th2) themselves mediated by Th2 cells. cells, such as interleukin-4 (IL-4), play a pivotal role on the Oral tolerance protocol is usually studied in naive animals.1 onset and maintenance of immunoglobulin E (IgE) responses.The evaluation in previously immunized animals is of parThis observation is the rationale for treatments of allergic ticular interest to the development of immunotherapeutic response that are based on the down-regulation of Th2 cell approaches for human allergic diseases. However, these studies functions.must take into account that oral administration of antigen to One of the protocols used to induce antigen-specific sysimmunized animals might occasionally enhance a pre-existing temic immune tolerance is based on the oral antigen adminisimmune response.11-13 We have previously shown that the oral tration followed by a challenge with the same antigen.1 administration of Dp has a more pronounced inhibitory effect Suppression of Th1-mediated inflammatory responses by oral in sensitized mice than in naive mice.14 The induction of oral administration of autoantigen has been observed in several tolerance is a complex process that is influenced by many autoimmune disease and transplantation models.2,3 Among factors, such as animal age, genetic background and dose and the oral tolerance applications, there is a special interest in the administration regimen of the tolerogen.15 modulation of the Th2-allergic-mediated diseases,4-7 since Th1In the present work, we investigated the effect of oral and Th2 cells can be inactivated by feeding antigen.8 administration of varying doses of dust mite extract in a CD4 lymphocytes have an important role on the regulation mu...