title: Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.
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.
authors.affiliation: 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;
authors.forename: Michela
authors.initials: M
authors.lastname: Frascoli
authors.affiliation: 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;
authors.forename: Cerine
authors.initials: C
authors.lastname: Jeanty
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143;
authors.forename: Shannon
authors.identifier: 0000-0002-5607-6819
authors.initials: S
authors.lastname: Fleck
authors.affiliation: 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;
authors.forename: Patriss W
authors.initials: PW
authors.lastname: Moradi
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118; and.
authors.forename: Sheila
authors.identifier: 0000-0002-8324-3694
authors.initials: S
authors.lastname: Keating
authors.affiliation: 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.
authors.forename: Aras N
authors.identifier: 0000-0002-5813-164X
authors.initials: AN
authors.lastname: Mattis
authors.affiliation: Department of Surgery, University of California San Francisco, San Francisco, CA 94143;
authors.forename: Qizhi
authors.identifier: 0000-0001-7313-3574
authors.initials: Q
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Tippi C
authors.initials: TC
authors.lastname: MacKenzie
mesh_terms: D000653:Amniotic Fluid / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054413:Chemokine CCL11 / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000628:therapy; D004804:Eosinophils / Q000276:immunology / Q000502:physiology; D005260:Female; D005312:Fetal Blood / Q000166:cytology / Q000276:immunology; D005315:Fetal Diseases / Q000276:immunology* / Q000628:therapy*; D046128:Fetal Therapies; D020139:Gastroschisis / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D007156:Immunologic Memory; D007231:Infant, Newborn; D007249:Inflammation / Q000628:therapy; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology*; D007422:Intestines / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D009035:Mothers; D011247:Pregnancy
chemical_list: D057134:Antibodies, Neutralizing; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D016207:Cytokines; D015848:Interleukin-5