Intraamniotic Lipopolysaccharide Exposure Changes Cell Populations and Structure of the Ovine Fetal Thymus

Kuypers, Elke; Wolfs, Tim G. A. M.; Collins, Jennifer J. P.; Jellema, Reint K.; Newnham, John P.; Kemp, Matthew W.; Kallapur, Suhas G.; Jobe, Alan H.; Kramer, Boris W.

doi:10.1177/1933719112472742

Cited by 34 publications

(40 citation statements)

References 55 publications

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“…Neonatal mononuclear cells are high producers of IL-23, while being poor IL-12 producers (52–54). Of note, our recent results in a sheep model showed relatively long-lasting effects of LPS-induced inflammation on the fetal thymus, as upregulation of IL-17 mRNA and down-regulation of FOXP3 mRNA persisted several days after the exposure (55). However, we acknowledge that such acute model of inflammation does not fully reproduce human chorioamnionitis, which is often a chronic fetal exposure to inflammatory challenges.…”

Section: Discussionmentioning

confidence: 91%

Intra-Amniotic IL-1β Induces Fetal Inflammation in Rhesus Monkeys and Alters the Regulatory T Cell/IL-17 Balance

Kallapur

Presicce

Senthamaraikannan

et al. 2013

The Journal of Immunology

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Very low birth weight preterm newborns are susceptible to the development of debilitating inflammatory diseases, many of which are associated with chorioamnionitis. To define the effects of chorioamnionitis on the fetal immune system, IL-1β was administered intra-amniotically at ∼80% gestation in rhesus monkeys. IL-1β caused histological chorioamnionitis as well as lung inflammation (infiltration of neutrophils or monocytes in the fetal airways). There were large increases of multiple pro-inflammatory cytokine mRNAs in the lungs 24 h post-administration, which remained elevated relative to controls at 72 h. Intra-amniotic IL-1β also induced sustained expression of the surfactant proteins in the lungs. Importantly, IL-1β significantly altered the balance between inflammatory and regulatory T cells (Treg cells). Twenty-four h after IL-1β injection, the frequency of CD3+CD4+FOXP3+ T cells was decreased in lymphoid organs. In contrast, IL-17A–producing cells (CD3+CD4+, CD3+CD4−, and CD3−CD4− subsets) were increased in lymphoid organs. The frequency of IFN-γ-expressing cells did not change. In this model of a single exposure to an inflammatory trigger, CD3+CD4+FOXP3+ cells rebounded quickly and their frequency was increased at 72 h compared to controls. IL-17 expression was also transient. Interestingly, the T cell profile alteration was confined to the lymphoid organs and not to circulating fetal T cells. Together, these results suggest the chorioamnionitis-induced IL-1/IL-17 axis is involved in the severe inflammation that can develop in preterm newborns. Boosting Treg cells and/or controlling IL-17 may provide a means to ameliorate these abnormalities.

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Section: Discussionmentioning

confidence: 91%

Intra-Amniotic IL-1β Induces Fetal Inflammation in Rhesus Monkeys and Alters the Regulatory T Cell/IL-17 Balance

Kallapur

Presicce

Senthamaraikannan

et al. 2013

The Journal of Immunology

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“…In experimental models of chorio, intraamniotic LPS or IL-1β decreased the frequencies of FOXP3 + cells in sheep thymus and lymph nodes [11,38,39]. In fetal rhesus macaques, a single intra-amniotic exposure of IL-1β also decreased the frequency of Treg at 24 h in spleen and lymph nodes, but not blood [40].…”

Section: Discussionmentioning

confidence: 99%

Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates

et al. 2015

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Regulatory T-cells (Treg) have a protective role for the control of immune activation and tissue damage. The effects of chorioamnionitis (chorio) on Treg in moderate/late preterm newborns are not known. We hypothesized that infants exposed to chorio would have decreased Treg frequency and/or function. We isolated mononuclear cells from adult peripheral blood and cord blood from term and moderate/late preterm infants who were classified for severity of chorio exposure. Mononuclear cells were analyzed by flow cytometry for Treg frequency and phenotype. Treg suppression of activation of conventional T-cells (Tcon) was also quantified. Treg frequencies were similar in all groups of neonates, but lower than that found in adults. Newborn Treg had a naïve phenotype, with decreased levels of CD45RO, HLA-DR, CD39 and TIGIT compared to adult Treg and chorio did not affect the phenotype. Treg from preterm newborns exposed to severe chorio had higher expression of Ki67 compared to the other groups. Treg from preterm newborns were less suppressive than Treg from adults or term, and the level of suppression was reduced with severe chorio. Relative to term, Treg frequency and phenotype were not affected by prematurity and chorio but their functionality was decreased. Lower Treg activity may contribute to inflammation in newborns that is often associated with chorioamnionitis.

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“…Interestingly, IL-6 has also been involved in some cases of thymus atrophy, as thymic depletion due to age [1] or fetal thymic atrophy caused by LPS treatment [18], indicating a possible link between IL-6 and thymic alterations.…”

Section: Introductionmentioning

confidence: 99%

Altered bone marrow lymphopoiesis and interleukin-6-dependent inhibition of thymocyte differentiation contribute to thymic atrophy during Trypanosoma cruzi infection

et al. 2017

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Thymic atrophy occurs during infection being associated with apoptosis of double positive (DP) and premature exit of DP and double negative (DN) thymocytes. We observed for the first time that a significant bone marrow aplasia and a decrease in common lymphoid progenitors (CLPs) preceded thymic alterations in mice infected with Trypanosoma cruzi. In addition, depletion of the DN2 stage was previous to the DN1, indicating an alteration in the differentiation from DN1 to DN2 thymocytes. Interestingly, infected mice deficient in IL-6 expression showed higher numbers of DP and CD4+ thymocytes than wild type infected mice, while presenting similar percentages of DN1 thymocytes. Moreover, the drop in late differentiation stages of DN thymocytes was partially abrogated in comparison with wild type littermates. Thus, our results suggest that thymic atrophy involves a drop in CLPs production in bone marrow and IL-6-dependent and independent mechanisms that inhibits the differentiation of DN thymocytes.

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Intraamniotic Lipopolysaccharide Exposure Changes Cell Populations and Structure of the Ovine Fetal Thymus

Cited by 34 publications

References 55 publications

Intra-Amniotic IL-1β Induces Fetal Inflammation in Rhesus Monkeys and Alters the Regulatory T Cell/IL-17 Balance

Intra-Amniotic IL-1β Induces Fetal Inflammation in Rhesus Monkeys and Alters the Regulatory T Cell/IL-17 Balance

Effect of chorioamnionitis on regulatory T cells in moderate/late preterm neonates

Altered bone marrow lymphopoiesis and interleukin-6-dependent inhibition of thymocyte differentiation contribute to thymic atrophy during Trypanosoma cruzi infection

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