Table 3.
Maternal protective and risk factors for offspring allergy in mouse models.
| Responsible factors | Strains | Treatment to dam | Dose/timing | Effects | References |
|---|---|---|---|---|---|
| IN UTERO | |||||
| Allergen | BALB/c, DO11.10 | · Oral administration · Oral administration |
· High-dose OVA (9 mg) during the first week of pregnancy · Low-dose OVA (1.5 mg) during pregnancy · Low-dose OVA (1.5 mg) during pregnancy |
· Suppression of OVA-specific IgE levels in 3-day-old, but not in 25-day-old, BALB/c offspring · Sustained inhibition of OVA-specific IgE levels both in 3- and 25-day-old BALB/c offspring ·In utero priming of offspring DO11.10-derived T cells |
(99) |
| · B cells · Allergen-IgG-IC |
C57BL/6, Mature B-cell-deficient μMT | Intranasal exposure | 500 μg OVA before conception | · Induction of tolerance in C57BL/6 offspring against allergic airway inflammation · Abolished preventive effects against allergic airway inflammation in μMT · OVA-IgG1-IC bound to FcγR and promoted differentiation of Foxp3+ Treg. |
(100) |
| Maternal IFN-γ | CD1 | i.p. injection with IFN-γ | 100 IU of recombinant IFN-γ during pregnancy | Maternal IFN-γ induced stronger protective effects when prenatally transferred in utero than when postnatally transferred via breast milk against allergic airway inflammation in offspring. | (101) |
| Maternal IgG and offspring IFN-γ | BALB/c, C57BL/6J, FcRn-deficient B6.129X1-Fcgrttm1Dcr | Oral administration | 100 mg OVA before conception | ·In utero IgG transfer decreased the disease severity in BALB/c offspring. · Offspring of FcRn-deficient dam nursed by OVA-fed C57BL/6 WT dams showed protective effects against OVA-induced asthma-like symptom. · Anti-IFN-γ treatment of offspring during sensitization and challenge with allergen abolished the protection. |
(102) |
| Maternal TLR signaling and offspring IFN-γ | BALB/c, C57BL/6 Tlr2/3/4/7/9−/− | Intranasal applications of freeze-dried A. lwoffii F78 suspended in PBS | 108 CFU of A. lwoffii F78 during prenatal period | · IFN-γ-dependent prevention of experimental asthma in BALB/c offspring · A significant reduction in acetylation levels of histone 4 of the Il4 promoter after OVA challenge · The preventive effect was completely abolished in heterozygous offspring of A. lwoffii F78-treated Tlr2/3/4/7/9−/− dam. |
(103, 104) |
| Maternal Th1-biased immunity | C57BL/6J | OVA with incomplete Freunt's adjuvant (s.c.) or alum (i.p.) | Preconceptionally immunized with 25 μg OVA with incomplete Freunt's adjuvant or 2 mg alum | · Offspring of dams with Th1-biased immunity showed reduced levels of OVA-specific IgE and airway eosinophilia compared with offspring of dams with Th2-biased immunity or naïve dams. · Suppression of allergic airway inflammation in offspring from Th1-biased dams was antigen-specific. |
(105) |
| Short-chain fatty acid, especially acetate | C57BL/6 | Fed with high-fiber diet or drinking water with acetate or propionate | · High-fiber diet: SF11-025 · 200 mM acetate or propionate |
· Offspring of dams fed high-fiber diet or acetate failed to develop allergic airway disease. · Dams showed significant changes in microbiota composition, which was accompanied by an increase in high-acetate-producing Bacteroidetes and short-chain fatty acids in their feces and serum. |
(106) |
| IL-4 signaling in asthmatic dams | BALB/c | Immunized with OVA/alum and exposed to OVA aerosol | Preconceptionally immunized with 5 μg OVA/1 mg alum and exposed to 3% (w/v) OVA aerosol during pregnancy | · Offspring of OVA-dams, but not of unsensitized dams, exhibited allergic airway inflammation in response to suboptimal sensitization with OVA/alum and OVA aerosol. · This model of maternal transmission of asthma susceptibility to offspring was not allergen-specific. |
(107) |
| Maternal allergen-specific T cells | BALB/c | Adoptive transfer of DO11.10-derived T cells to naive dams | 5 ×106 DO11.10 T cells/mouse i.p. at 3 days before mating | · Higher responsiveness of offspring to suboptimal challenge of OVA · Donor T cells were identified in spleen and placenta of the recipient female dams but were not detectable in fetal tissues. |
(108) |
| CD25 and GITR | BALB/c | · Depletion of CD25high T cell population in 4-day-old newborn mice before induction of airway inflammation · Anti-GITR antibody treatment before induction of airway inflammation with suboptimal sensitization protocol · Anti-GITR antibody treatment after induction of airway inflammation |
· Increased susceptibility to allergic airway inflammation in normal offspring · Substantial reduction in asthma symptoms in offspring of allergic dams · Significant attenuation of the susceptibilities to allergic airway inflammation in offspring of both naïve and asthmatic dams · Enhanced asthma-like allergic inflammation in normal offspring · Slight deterioration of allergic airway inflammation in the offspring of asthmatic dams |
(109) | |
| Skin barrier impairment | Offspring of male Flgft/ft/Tmem79ma/ma and female C57BL/6 | i.p. sensitization with OVA/alum and exposure to OVA aerosols (C57BL/6 WT dam) | 5 μg OVA/1 mg alum and exposed to 3% (w/v) OVA aerosol before mating with unsensitized flaky tail male mice | · Increase in food allergen sensitization, serum mMCP1, and anaphylaxis to food allergen sensitization · Associated with higher levels of transcripts for CCL11, TSLP and IL-33 in skin, and TSLP in jejunum |
(110) |
| BREASTFEEDING | |||||
| Allergen in breast milk | BALB/c | Airborne allergen exposure | 0.5% OVA every other day during lactation | · Intact OVA and its degraded products were detectable in breast milk. · Offspring of OVA-exposed dams showed a significant protection against allergic airway inflammation, production of antigen-specific IgE, IgG1, and IgA antibodies, allergen-specific secretion of Th2 cytokines and IL-10 compared to offspring of unexposed dams. · The decrease in the disease susceptibility in offspring was independent on maternal Igs or IL-10. |
(111) |
| Maternal TGF-β during breastfeeding and infant IFN-γ | BALB/c | Oral administration | 2 mg OVA three times a week in the first, second, and third week of or throughout breastfeeding | · Oral tolerance induction in offspring were completely abolished in those nursed by dams treated with anti-TGF-β monoclonal antibodies. · Oral tolerance induction in offspring of OVA-fed dams was insufficient in 1-week-old neonates, accompanied by a reduction in gut barrier, retinaldehyde dehydrogenase expression by mesenteric lymph node CD103+ neonatal DCs. · One-week-old neonates were refractory to oral tolerance elicited by maternal allergen transfer via milk due to a physiological vitamin A deficiency. · Vitamin A supplementation rescued these neonatal defects and induced efficient tolerance in 1-week-old mice. · Oral tolerance was also dependent on offspring IFN-γ. |
(111, 112) |
| IgG-IC | BALB/c | · OVA/alum i.p. · Exposure of OVA aerosols |
· 10 μg OVA/2 mg alum, preconceptionally · 0.3% OVA during breastfeeding |
· Induced a long-lasting allergen-specific protection from asthma. · OVA-IgG-IC transferred into offspring by FcRn was associated with the differentiation of Foxp3+ Treg cells in offspring. · OVA-specific DO11.10-derived T cells co-cultured with bone marrow-derived DCs proliferated and upregulated Foxp3 expression in vitro in the presence of breast milk from OVA-exposed dams or · OVA-IgG-IC purified from breast milk. · OVA-IgG-IC induced the proliferation of DO11.10-derived T cells at least 100-fold more efficiently than OVA alone. · Milk IC-mediated tolerance was more profound than the tolerance induced by milk-borne free allergen and did not require TGF-β, IgA, or FcγRIIb. |
(18) |
| IgG1 and FcRn in offspring | B-cell deficient Igh6tm1Cgn, C57BL6/J, FcRn-deficient Fcgrt−/− | ·i.p. injection with OVA/alum · OVA aerosol |
· 25 or 8 μg OVA/2 mg alum before mating · 1% OVA dairy before mating and during embryonic days 11–17 of pregnancy |
· Offspring nursed by B-cell deficient Igh6tm1Cgn mice failed to show protection against OVA-specific IgE production and OVA-induced allergic airway inflammation. ·Fcgrt−/− offspring nursed by OVA-sensitized WT dams exhibited 1/1,000 to 1/10,000 lower levels of maternal OVA-specific IgG1 than those in similarly nursed Fcgrt+/− or WT offspring and failed to show protection against OVA-specific IgE production and allergic airway inflammation. | (113, 114) |
| Amount of allergen directly taken by infant | C3H/HeJ | Peanut exposure by gavage | 10 mg/mouse ground peanut three times a week for 4 weeks prior conception or preconceptionally and during pregnancy and breastfeeding | · No influence of maternal peanuts exposure during pregnancy on offspring peanut sensitization · Enhanced peanut-allergen uptake by CD11c+ DCs in Peyer's patch subepithelial dome in coadministration of peanut extract with breast milk from allergic dams as compared to coadministration of that from naïve dams · Oral administration of small dose (1 mg) of peanut extract to offspring with breast milk from sensitized or naïve dams during post-weaning period failed to enhance the induction of tolerance compared to those orally administered peanut extract alone in offspring. |
(115) |
| Low dose allergen exposure during pregnancy and lactation | C3H/HeJ | Oral peanut/CT exposure by gavage | · 10 mg/mouse ground peanut/20 μg/mouse CT weekly and peanut exposure (50 mg/mouse) preconceptionally · 10 mg/mouse ground peanut/20 μg/mouse CT preconceptionally and during pregnancy and breastfeeding |
· Offspring of dams preconceptionally sensitized with peanut/CT exhibited maternal IgG1-mediated anaphylaxis in response to oral peanut challenge. · Offspring were protected from anaphylaxis following first peanut challenge as well as active peanut/CT sensitization and oral peanut challenge. |
(17) |
| Allergens and allergen- specific immunoglobulins | BALB/c | ·i.p. injection of OVA/alum · Oral administration of OVA |
· 50 μg OVA/1.3 mg alum twice at 2-week interval periconceptionally · 1% OVA in drinking water during breastfeeding for 2 weeks |
· Offspring of OVA-sensitized and challenged dams showed the most significant reduction in food allergic responses, as indicated by a decrease in levels of diarrhea occurrence, OVA-specific IgE, Il4 mRNA expression, and numbers of mucosal mast cells in proximal colon compared to those in offspring from naïve dams. · Offspring from dams unsensitized and challenged with OVA exhibited a partial but a significant reduction in food allergic responses compared to those from naïve dams. · Offspring from OVA-sensitized dams without oral OVA challenge showed comparable food allergic responses to offspring of naïve dams. |
(116) |
| Oral TGF-β supplementation after weaning | BALB/c | ·i.p. injection of OVA/alum · Oral administration of OVA |
· 10 μg OVA/ 2 mg alum. twice at 1-week interval at 2 days before mating · 2 mg OVA by gavage three times a week during lactation |
· Offspring of naïve dams nursed by OVA-sensitized dams showed a significant reduction in levels of diarrhea score, serum mMCP1, and OVA-specific IgE antibodies compared to naïve offspring nursed by naïve dams. · Breastfeeding by OVA-dams decreased the frequencies of allergic diarrhea in response to multiple oral OVA challenges in 6-week-old, but not in 13-week-old offspring. · Supplementation with TGF-β after weaning till 12-week prolonged protection against diarrhea and improved gut barrier in 13-week-old mice breastfed by OVA-dams. |
(117) |
| Maternal OVA IgG-IC and offspring FcRn | BALB/c, FcRn-deficient Fcgrt−/− | · Epicutaneous sensitization ·i.p. injection of OVA-IgG1-IC | · 100 μg OVA preconceptionally and during pregnancy and breastfeeding · 100 μg OVA-IgG1-IC once weekly for 3 weeks during breastfeeding |
· Maternal allergen sensitization through skin prevented food anaphylaxis, allergen-specific IgE production, serum IL-4, serum mMCP1, and intestinal mast cell expansion in BALB/c offspring. · The protective effects of food allergy by OVA-sensitized dam were abolished in Fcgrt−/−. · Offspring of naïve dams supplemented with OVA-IgG1-IC showed increase of serum OVA-IgG1-IC levels, OVA-specific Treg in mesenteric lymph node at weaning, and protection against food allergy. |
(74) |
| Th2-biased epigenetic alteration | C3H/HeJ | Intragastric | 10 mg peanut/20 μg CT weekly for 5 weeks and 200 mg peanut at 6 weeks before conception | Offspring of dams sensitized and challenged with peanut exhibited increased food allergic responses following suboptimal dose of oral peanut/CT sensitization and peanut challenge, associated with hypomethylation at CpG sites of Il4 gene promoter. | (118) |
A. lwoffii, Acinetobacter lwoffii; CCL, C-C motif chemokine ligand; CFU, colony forming unit; CT, cholera toxin; DC, dendritic cell; FcγR, Fc gamma receptor; FcRn, neonatal Fc receptor; Foxp3, forkhead box p3; GITR, glucocorticoid-induced tumor necrosis factor receptor-family related receptor; IC, immunecomplex; IFN, interferon; Ig, immunoglobulin; IL, interleukin; i.p., intraperitoneal; IU, international unit; mMCP1, mouse mast cell protease I; OVA, ovalbumin; PBS, phosphate buffered saline; s.c., subcutaneous; TGF-β, tumor growth factor β; Th, helper T cell; TLR, toll-like receptor; Treg, regulatory T cell; TSLP, thymic stromal lymphopoietin; WT, wild type.