The majority of PNA reactions occur at first known PN ingestion.(5
) Although little is known about risk factors, it has been suggested that food allergy, including PNA, is associated with maternal allergy. (6
) However, there is no direct evidence showing that maternal PNA increases development of PNA in offspring. Our study is the first attempt to determine the effect of maternal PNA on first exposure PN reactions of offspring in a mouse model. We found that 5-week-old C3H/HeJ mice of PNA-M developed anaphylactic reactions following the first PN challenge. A PAF antagonist, but not a histamine antagonist, completely blocked these reactions. An association between PAF and severe human anaphylactic reactions, including fatal anaphylaxis in PNA patients has been reported.(32
) In this study, we also found that histamine and MMCP-1 levels increased during the anaphylactic reactions. A previous study reported that PN can contribute to anaphylactic shock by activating complement, C3a. (33
) We speculate that although PAF appeared to be critical in these model, other mechanisms may also be involved. Further studies are required to clarify the mediators and cell types involved in anaphylaxis in this model. Finkelman has suggested two independent mechanisms involved in anaphylaxis, the classical pathway that is mediated by IgE antibody and alternative pathway that is mediated by IgG (IgG1) antibody. Because IgG but not IgE can cross the placenta, and offspring of PNA-M were fed PN free chow, were not actively sensitized with PN, and exhibited no detectable serum PN-IgE, but a high PN-specific IgG1, we hypothesized that the first exposure PN reactions in this model were mediated not by in utero PN sensitization but by transfer of maternal PN-specific IgG1. Although further work is needed to confirm this hypothesis, our finding that PCA reactions induced by heat-inactivated sera from PNA-M offspring at least suggest the role of IgG1 mediated reactions in this model. This finding is consistent with previous findings in which IgG1 mediated murine anaphylactic reaction in the absence of IgE.(29
) However, whether this mechanism also accounts for first-exposure reactions to PN in children is unknown and remains to be investigated. Most human anaphylaxis is IgE dependent, but, as noted by Finkelman, there is evidence that human anaphylaxis can also be IgG mediated.(29
) Bock et al.(34
) examined the natural history of adverse reactions to foods in 480 children followed from birth to their third birthday. During the first year of life, 80% of the initial complaints of food reactions occurred and almost all reproducible reactions appeared to be non IgE mediated. Niggemann et al(35
) reported a subgroup of children with positive double blind, placebo controlled food challenge responses with no proven IgE sensitization. Whether non-IgE mediated food allergic reactions are IgG mediated remains to be defined.
Maternal avoidance of PN during pregnancy and lactation was recommended for many years in the US and UK. Recently, this recommendation has been abandoned because of lack of conclusive evidence of benefit,(9
) and evidence that this approach may increase the risk of PNA development.(2
) Hourihane et al (27
) reported peanut allergy outcomes in a cohort of children born after the UK government's advice to mothers of high-risk infants to follow maternal avoidance during pregnancy and lactation, and to avoid introduction of peanut to their children until age 3 years. The rate of peanut allergy in this cohort was 1.8%, the highest recorded. Several studies indicated that early introduction of peanuts to infants may be beneficial.(2
) However whether maternal exposure to controlled low dose of PN prevents high-risk children from developing PNA is unknown. Our study is the first attempt to investigate the possible beneficial effect of maternal PN exposure during pregnancy and lactation in preventing/reducing PNA in high risk offspring in a mouse model in which it is known that IgG1 can precipitate a reaction. We found that weekly exposure of PNA-M to a low dose of PN (beneath the threshold of triggering clinical reactions) during pregnancy and lactation (PNA-M/PN) reduced first PN exposure reaction. This protection was associated with dominant IgG2a antibodies. As in previously reported studies in murine models,(17
) we employed adjuvant, cholera toxin, to enhance the response to PN antigen exposure. We found that giving PN plus adjuvant during pregnancy and lactation was more effective in preventing PNA development in offspring than PN alone (López-Expósito et al and Song et al. unpublished data). As primary intervention for high risk offspring, maternal low dose exposure during pregnancy and lactation with PN plus a more Th1 driven adjuvant such as CpG ODN should be addressed in the future. Furthermore, one may question whether pregnant women with PNA should consume any PN because of concern of severe reactions. However, Clark et al(36
) recently showed that peanut oral immunotherapy (OIT) can induce clinical tolerance to PN protein in humans. In this study, a marked increase in PN dose threshold was observed; from 5–50 mg (1/40–1/4 of a whole peanut) at pre OIT to at least 2.38 g protein (10 whole peanuts) post OIT. If this approach can be reproduced in large controlled study, it is possible that PNA women who are able to develop PN tolerance following OIT(36
) or other interventions,(21
) should be able to continue PN at a maintenance dose during pregnancy and lactation.
We found no evidence of maternal PN-specific T cell transmission, because there was no detectable PN-specific cytokine production by splenocytes from either PNA-M/PN or PNA/M-None offspring. Importantly, T cell suppression was observed in offspring of PNA-M/PN as evidenced by overall inhibition of mitogen-stimulated cytokine production. These findings prompted us to test possible inhibition of IgE synthesis of these offspring following active PN sensitization. We found a marked elevation of PN-specific IgE in offspring of PNA-M/None offspring as early as 3 wks following PN-sensitization, which was more than 10 fold high than naïve mice offspring in respond to PN-sensitization (data not shown). However, there was an overall suppression of PN-specific IgE as well as IgG1 and IgG2a synthesis in PNA-M/PN offspring at 3 weeks following active PN sensitization. However, PN-specific IgE, IgG1 and IgG2a in PNA-M-PN offspring developed following PN-sensitization at wk 6, although the levels were significantly lower than those of PNA-M/None offspring. These data demonstrated a short window of unresponsiveness (tolerance) to PN-sensitization. The mechanisms underlying reduced responsiveness (tolerance) in PNA-M/PN offspring following peanut sensitization was not investigated in this study. There are several potential explanations. First it may be mediated by T regulatory cells or low dose antigen transmitted by breast milk as a previous study showed breast milk-mediated transfer of an antigen induces tolerance and protection from allergic asthma (18
); Second, it may be due to CD80-CTLA-4 interactions, because a previous study suggested that CD80, but not CD 86 interaction with CTLA-4 is crucial for the induction of low dose tolerance to PN. (39
) It may also be due to T cell anergy, as it has been shown that immature dendritic cells (DCs), which encounter antigen in the absence of inflammation, cause T cells anergy, while mature DCs, which encounter antigen in the presence of inflammation induce development of effector T cells. (40
) Further characterizing of the mechanisms underlying the induction of offspring tolerance to PN sensitization by exposure PNA-M to low dose PN during pregnancy and lactation is required.
Taken together, this study demonstrated that maternal PNA is a risk factor for developing PNA. Low dose PN-exposure during pregnancy and lactation reduced the risk of first exposure PN anaphylaxis and specific IgE production to active PN sensitization in offspring. Although murine models are not identical to human disease, our work may provide a rationale for a new concept regarding prevention of PNA in offspring of PN allergic women. More studies are required to further understand the underlying mechanisms.