The domestic pig as human‐relevant large animal model to study adaptive antifungal immune responses against airborne <i>Aspergillus fumigatus</i>

Schmidt, Stefanie; Ebner, Friederike; Rosen, Kerstin; Kniemeyer, Olaf; Brakhage, Axel A.; Löffler, Jürgen; Seif, Michelle; Springer, Jan; Schlosser, Josephine; Scharek‐Tedin, Lydia; Scheffold, Alexander; Bächer, Petra; Kühl, Anja A.; Rösler, Uwe; Hartmann, Susanne

doi:10.1002/eji.201948524

Cited by 7 publications

(4 citation statements)

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“…Consistent with animal studies showing that extensive or serial exposure of healthy mice or piglets to A. fumigatus conidia led to a co-expansion of various Th cell subsets [26,27], our cohort of organic farmers without known mold-associated hyperinflammatory diseases displayed a comparable increase in AfuLy-reactive Th1 and Th2 cells. Accordingly, ELISPOT and WB-based Luminex assays revealed marked induction of A. fumigatus antigen-reactive Th1-and Th2-cell-derived cytokines in organic farmers, whereas differences in IL-17 levels were much smaller between the two cohorts.…”

Section: Discussionsupporting

confidence: 88%

Chronic Occupational Mold Exposure Drives Expansion of Aspergillus-Reactive Type 1 and Type 2 T-Helper Cell Responses

Lauruschkat

Etter

Schnack

et al. 2021

JoF

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Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.

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Section: Discussionsupporting

confidence: 88%

Chronic Occupational Mold Exposure Drives Expansion of Aspergillus-Reactive Type 1 and Type 2 T-Helper Cell Responses

Lauruschkat

Etter

Schnack

et al. 2021

JoF

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“…Similar to the application of CD154 as a marker of Th cell activation in mice ( 17 , 19 ), humans ( 8 , 41 ), and pigs ( 25 , 26 ), we demonstrated its suitability for equine Th cells and identified specific cross-reactivity of the anti-human antibody 5C8 with equine CD154. The main stimulation effect of SEB or PMA combined with ionomycin on membrane-bound CD154 (38 kDa) detection in Western blots matches the use of cell lysates in this experiment.…”

Section: Discussionmentioning

confidence: 63%

“…In this study, an anti-human CD154 antibody was used for the confirmation of r equine CD154 protein expression ( 20 ). In humans and pigs CD154 has been used as an indicator of antigen-specific T cell activation and for the enrichment of reactive T cells ( 8 , 15 , 16 , 25 , 26 ), detected with another anti-human CD154 monoclonal antibody (mAb), clone 5C8 ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

CD154 Expression Indicates T Cell Activation Following Tetanus Toxoid Vaccination of Horses

et al. 2022

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Despite the relevance of adaptive immunity against equine pathogens antigen-specific T cell responses of horses are not well characterized and the lack of insight into T cell responses hampers the understanding of the pathogeneses of important diseases. In this study we used tetanus toxoid (TT) as a well-defined antigen to characterize antigen-reactive T cells. Six healthy adult horses received a routine booster against tetanus with an immune stimulating complex (ISCOM)-based vaccine and were followed for 28 days. TT-specific serum antibodies were quantified by ELISA and increased in all horses by day 7 after vaccination. CD154 is an established indicator of antigen-reactive T helper cells in other species, but has not been characterized in horses. CD154 detection in equine PBMC by an anti-human CD154 antibody (clone 5C8) was confirmed by Western blots and then applied for flow cytometry. As a common indicator of equine T cell activation, cytokine induction was studied in parallel. T cells were analyzed by multicolor flow cytometry of PBMC after re-stimulation with TT in vitro. Reactive T helper (Th) cells were characterized by increased frequencies of CD4+CD154+ lymphocytes in in vitro TT-re-stimulated PBMC on day 14 after vaccination of the horses compared to pre-vaccination. The majority of all CD154+ cells after TT re-stimulation were CD4+ Th cells, but CD154 was also induced on CD4- cells albeit in lower frequencies. CD154+CD4+ Th cells were enriched in cytokine-expressing cells compared to CD154-CD4+ Th cells. Similar to the CD4+CD154+ frequencies, CD4+IL-4+, CD4+IFN-γ+ and CD4+TNF-α+ were increased after vaccination, but IL-4+ increased later than IFN-γ+ and CD4+TNF-α+, which already exceeded pre-vaccination frequencies on day 7. CD4+CD154+ frequencies correlated positively with those of CD4+IL-4+ (Th2) on day 14, and negatively with CD4+IFN-γ+ induction on day 7, but did not correlate with CD4+TNF-α+ frequencies or TT-specific antibody concentrations. CD154 appears to be a useful marker of antigen-reactive equine Th cells in combination with cytokine expression. The T cell analyses established here with TT can be applied to other antigens relevant for infections or allergies of horses and in horse models for translational research.

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“…However, studies in humans investigating early changes of lung development are restricted due to ethical reasons and limited access to tissue material. For human medicine, the pig represents a promising biomedically relevant animal model with important anatomical, physiological, and immunological similarities to the human respiratory tract (19)(20)(21). Ontogenetically, lung development in pigs is very similar to that of humans (8).…”

Section: Introductionmentioning

confidence: 99%

Influence of Nutrition and Maternal Bonding on Postnatal Lung Development in the Newborn Pig

Schlosser-Brandenburg

Ebner

Klopfleisch

et al. 2021

Front. Immunol.

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BackgroundMicrobial colonization and immune cell maturation coincide at mucosal sites and are decisive for postnatal lung development. How external factors influence neonatal pulmonary immune development is poorly understood.ObjectiveTo elucidate the impact of key determinants in early life, nutrition, and maternal bonding, on postnatal lung maturation in a human-relevant animal model. To investigate the underlying immunological changes of impaired lung maturation and study the mechanisms of conversion.MethodsNewborn piglets were kept with or without isolation from their mothers and fed bovine milk-based infant formula or received milk of sow. Lung growth, histomorphology, respiratory immune responses, and lung microbiota were analyzed. Mother- and sow-milk-deprived piglets received maternal material or were reintroduced to the maternal environment at varying intervals to study options for reversal.ResultsFormula feeding combined with isolation of newborn piglets resulted in disturbed postnatal lung maturation. Reduced lung growth correlated with dampened IL-33 expression, impaired lung myeloid cell activation, and decreased Th1 differentiation, along with diminished richness and diversity of the lung microbiota. Transfer of bacteria-enriched maternal material reversed the negative effects on pulmonary immune maturation. Early (within 3 days) but not late (within 7 days) reintroduction to the mother allowed restoration of normal lung development.ConclusionOur findings reveal that lung growth, respiratory immunity, and microbial lung colonization in newborns depend on postnatal diet and maternal contact, and targeting these key regulators could promote lung development during this critical life stage.SummaryDisturbances in natural diet and reduced maternal contact during the neonatal period impair postnatal lung maturation. In pediatrics, timely breast milk feeding and intensive maternal bonding represent valuable intervention measures to promote early postnatal lung development.

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The domestic pig as human‐relevant large animal model to study adaptive antifungal immune responses against airborne Aspergillus fumigatus

Cited by 7 publications

References 50 publications

Chronic Occupational Mold Exposure Drives Expansion of Aspergillus-Reactive Type 1 and Type 2 T-Helper Cell Responses

Chronic Occupational Mold Exposure Drives Expansion of Aspergillus-Reactive Type 1 and Type 2 T-Helper Cell Responses

CD154 Expression Indicates T Cell Activation Following Tetanus Toxoid Vaccination of Horses

Influence of Nutrition and Maternal Bonding on Postnatal Lung Development in the Newborn Pig

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