Fetal Phagocytes Take up Allergens to Initiate T-Helper Cell Type 2 Immunity and Facilitate Allergic Airway Responses

Chen, Jeng-Chang; Chan, Chiu‐Po; Wu, Chia-Jen; Ou, Liang-Shiou; Yu, Hsiu-Yueh; Chang, Hsueh‐Ling; Tseng, Li-Yun; Kuo, Ming‐Ling

doi:10.1164/rccm.201508-1703oc

Cited by 14 publications

(26 citation statements)

References 49 publications

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“…5 However, their development lags far behind that of B or T-cells. 6 Macrophages emerge early on gestational day 9.5 -10.5 (GD 9.5-10.5 ) in mice 7 8 and week 5 in humans 9 as the first immune cells capable of surveying their surroundings and eliminating nonself antigens, particles or dead cells in fetal life. 7 10 They might play a role in tumor immune surveillance during embryo development.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous studies, prenatal exposure to ovalbumin (OVA) came to the development of Th2-skewed immunity. 9 This event could be attributed to fetal macrophagelike phagocytes (MPs) that sequestered the endocytosed OVA and differentiated toward dendritic cells to later instruct T-cells as they Open access fully developed to more efficiently deal with antigens. It implied that MPs were functionally important for shaping fetal immune responses.…”

Section: Introductionmentioning

confidence: 99%

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Fetal exposure to oncoantigen elicited antigen-specific adaptive immunity against tumorigenesis

Chen

Kuo

et al. 2020

J Immunother Cancer

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BackgroundEnvisioned as a similar process to tumorigenesis in terms of biological behaviors and molecular basis, embryogenesis necessitates an immune surveillance system to eliminate erratically transformed cells. Our previous study demonstrated that fetal macrophage-like phagocytes triggered Th2-skewed immunity following endocytosing prenatally administered ovalbumin to facilitate postnatal allergic airway responses, highlighting the critical role fetal phagocytes played in dealing with antigens present in developing fetuses and shaping subsequent immune responses. It prompted us to examine whether fetuses could mount Th1 tumoricidal immunity against tumorigenesis following in utero exposure to tumor antigens.MethodsGestational day 14 murine fetuses underwent in utero injection of Th1-promoting human papilloma virus (HPV) E7 peptides. Postnatally, recipients were examined for immunological consequences and the resistance to TC-1 tumorigenesis.ResultsFetal exposure to HPV E7 did not cause tolerance but rather immunization in the recipients, characterized by proinflammatory Th1 polarization of their lymphocytes. Fetal macrophage-like phagocytes were responsible for taking up HPV E7 and triggering HPV E7-specific T-cell cytotoxicity and humoral immunity that rendered recipients resistant to TC-1 tumorigenesis in postnatal life. Adoptive transfer of HPV E7-loaded fetal phagocytes also elicited Th1 immunity with rapid expansion of HPV E7-specific cytotoxic CD8+ T-cell clones in response to TC-1 cell challenge so as to protect the recipients from TC-1 tumorigenesis, but failed to completely eliminate pre-existing TC-1 cells despite perceptible attenuation of local TC-1 tumor growth.ConclusionsOur study revealed that Th2-biasing fetus was not immune-privileged to foreign peptides, but competent to mount Th1 cytotoxic immunity and generate immunoglobulins against tumorigenesis following in utero exposure to Th1-promoting oncoantigen. It shed light on the role of fetal macrophage-like phagocytes in bridging toward tumor antigen-specific cellular and humoral immunity potentially as an immune surveillance system to eliminate transformed cells that might be egressing during embryogenesis and leftover until postnatal life.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fetal exposure to oncoantigen elicited antigen-specific adaptive immunity against tumorigenesis

Chen

Kuo

et al. 2020

J Immunother Cancer

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“…Prior sensitization of female mice to Aspergillus fumigatus extract, and re-exposure during early pregnancy increased airway eosinophilia, and IL-4 promoter hypomethylation in grandoffspring of exposed mothers 33 . Intra-uterine injection of OVA or house dust mite (HDM)-derived related proteins (Der P2) at very high concentrations (>5 μg) triggered the development of fatal anaphylaxis and pronounced airway dysfunction in exposed fetuses 34 . However, OVA is not an aeroallergen, A. fumigatus exposure is not predictive of asthma development in humans 35 , the co-administration of alum makes it difficult to determine whether the observed effects are allergen or adjuvant-driven and while allergen has been detected in the amniotic fluid in humans, it is typically present at ng/ml concentrations 36 .…”

Section: Introductionmentioning

confidence: 99%

Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring

Richgels

Yamani

Chougnet

et al. 2017

Journal of Allergy and Clinical Immunology

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Background Atopic status of the mother and maternal exposure to environmental factors is associated with increased asthma risk. Moreover, animal models demonstrate that exposure to allergens in strongly sensitized mothers influences offspring asthma development, suggesting that in utero exposures can influence offspring asthma. However, it is unclear whether maternal exposure to common human allergens like house dust mite (HDM), in the absence of additional adjuvants, influences offspring asthma development. Objective To determine if maternal HDM exposure influences asthma development in offspring. Methods Pregnant female mice were exposed to PBS or HDM during pregnancy. Using offspring of PBS or HDM-exposed mothers, the magnitude of HDM or Aspergillus fumigatus (AF) extract-induced airway hyperresponsiveness (AHR), airway inflammation, immunoglobulin production, Th2-associated cytokine synthesis and pulmonary dendritic cell activity was assessed. Results Compared to offspring of PBS-exposed mothers, offspring of HDM-exposed mothers demonstrate increased AHR, airway inflammation, Th2 cytokine production, immunoglobulin levels and a modest decrease in the phagocytic capacity of pulmonary macrophage populations following HDM exposure. Increased sensitivity to AF-induced airway disease was not observed. Offspring of HDM-exposed B cell deficient mothers also demonstrated increased HDM-induced AHR, suggesting transfer of maternal immunoglobulins is not required. Conclusions Our data demonstrate that maternal exposure to HDM during pregnancy increases asthma sensitivity in offspring in an HDM-specific manner, suggesting that vertical transmission of maternal immune responses may be involved. These findings have important implications for regulation of asthma risk, and suggest that exposure to HDM in the developed world may have under-appreciated influences on the overall prevalence of allergic asthma.

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“…Having worked on fetal tolerization over the years, we came to question aspects of “actively acquired tolerance” theory especially when our attempt at allergen desensitization through in utero ovalbumin exposure ended up with an event of in utero sensitization ( 57 ). Such an unexpected result could be attributed to macrophage-like fetal phagocytes that sequestered endocytosed ovalbumin for delayed antigen presentation.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, BMCs containing hematopoietic stem cells might represent a unique kind of in utero inocula, capable of conferring significant hematopoietic chimerism and long-lasting skin tolerance. Taken together with the discovery of in utero sensitization to soluble peptides of ovalbumin ( 57 ), the classical school of thought claiming that an early enough in utero contact with foreign antigens caused tolerance might oversimplify the situation. Conclusively, the immunological outcome of fetal exposure to foreign antigens might vary according to the type or nature of antigens introduced.…”

Section: Discussionmentioning

confidence: 99%

In Utero Exposure to Exosomal and B-Cell Alloantigens Lessens Alloreactivity of Recipients’ Lymphocytes Rather than Confers Allograft Tolerance

Chen

Chan

et al. 2018

Front. Immunol.

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According to actively acquired tolerance, antigen exposure before full immune development in fetal or early neonatal life will cause tolerance to this specific antigen. In this study, we aimed to examine whether allogeneic tolerance could be elicited by in utero exposure to surface MHC antigens of allogenic cells or soluble form of MHC exosomes. Gestational day 14 FVB/N fetuses were subjected to intraperitoneal injection of allogeneic major histocompatibility complex (MHC) exosomes or highly enriched B-cells. Postnatally, the recipients were examined for the immune responses to donor alloantigens by lymphocyte proliferative reactions and skin transplantation. In utero exposure to allogeneic MHC exosomes abolished the alloreactivity of recipients’ lymphocytes to the alloantigens, but could not confer skin allograft tolerance. In utero transplantation of highly enriched allogeneic B-cells generated low-level B-cell chimerism in the recipients. However, it only extended the survivals of skin allograft by a few days despite the lack of donor-specific alloreactivity of recipients’ lymphocyte. Thus, an early in utero contact with exosomal or B-cell alloantigens did not lead to full skin tolerance but rather, at best, only to delayed skin rejection in the presence of microchimerism made by B-cell inocula. These results argued against the theory of actively acquired tolerance, and implicated that in utero exposure to marrow cells in previous studies was a unique model of allo-tolerance induction that involved the establishment of significant hematopoietic chimerism. Taken together with the discovery of in utero sensitization to ovalbumin in our previous studies, the immunological consequences of fetal exposure to foreign antigens might vary according to the type or nature of antigens introduced.

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Fetal Phagocytes Take up Allergens to Initiate T-Helper Cell Type 2 Immunity and Facilitate Allergic Airway Responses

Abstract: Our results have mechanical implications for prenatal imprinting of atopy and shed light on the importance of fetal phagocytes in shaping the developing immune system and initiating allergic airway diseases.

Cited by 14 publications

References 49 publications

Fetal exposure to oncoantigen elicited antigen-specific adaptive immunity against tumorigenesis

Fetal exposure to oncoantigen elicited antigen-specific adaptive immunity against tumorigenesis

Maternal house dust mite exposure during pregnancy enhances severity of house dust mite–induced asthma in murine offspring

In Utero Exposure to Exosomal and B-Cell Alloantigens Lessens Alloreactivity of Recipients’ Lymphocytes Rather than Confers Allograft Tolerance

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