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J Immunol. 2016 Jun 15;196(12):4957-66. doi: 10.4049/jimmunol.1502587. Epub 2016 May 13.

Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143; Department of Surgery, University of California San Francisco, San Francisco, CA 94143;
2
Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143;
3
Blood Systems Research Institute, San Francisco, CA 94118; and.
4
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143; Department of Pathology, University of California San Francisco, San Francisco, CA 94143.
5
Department of Surgery, University of California San Francisco, San Francisco, CA 94143;
6
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143; Department of Surgery, University of California San Francisco, San Francisco, CA 94143; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143; Tippi.Mackenzie@ucsf.edu.

Abstract

The development of the fetal immune system during pregnancy is a well-orchestrated process with important consequences for fetal and neonatal health, but prenatal factors that affect immune activation are poorly understood. We hypothesized that chronic fetal inflammation may lead to alterations in development of the fetal immune system. To test this hypothesis, we examined neonates with gastroschisis, a congenital abdominal wall defect that leads to exposure of the fetal intestines to amniotic fluid, with resultant intestinal inflammation. We determined that patients with gastroschisis show high systemic levels of inflammatory cytokines and chemokines such as eotaxin, as well as earlier activation of CD4(+) and CD8(+) effector and memory T cells in the cord blood compared with controls. Additionally, increased numbers of T cells and eosinophils infiltrate the serosa and mucosa of the inflamed intestines. Using a mouse model of gastroschisis, we observed higher numbers of eosinophils and both type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), specifically in the portion of organs exposed to the amniotic fluid. Given the role of IL-5 produced by ILC2 in regulating eosinophil development and survival, we determined that maternal or fetal administration of the anti-IL-5 neutralizing Ab, or a depleting Ab against ILCs, can both effectively reduce intestinal eosinophilia. Thus, a congenital anomaly causing chronic inflammation can alter the composition of circulating and tissue-resident fetal immune cells. Given the high rate of prenatal and neonatal complications in these patients, such changes have clinical significance and might become targets for fetal therapy.

PMID:
27183609
PMCID:
PMC4977025
DOI:
10.4049/jimmunol.1502587
[Indexed for MEDLINE]
Free PMC Article

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