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

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.

The many faces of hydrops.

PURPOSE: Fetal hydrops arises from multiple disease processes and can portend a grim prognosis. We reviewed our experience with hydropic fetuses to understand relevant antenatal anatomic and physiologic predictors of survival. METHODS: We reviewed fetal ultrasounds and echocardiograms of hydropic fetuses evaluated from 1996 to 2013. RESULTS: Overall neonatal survival in 167 fetuses was 44% (range, 0-75%) and was influenced by the underlying disease process. The anatomic distribution of fluid varied and was not significantly different between survivors and nonsurvivors. Univariate analysis indicated that resolution of hydrops and delivery at a later gestational age were predictive of survival (OR: 5.7 (95% CI: 2.5-13.2) and OR: 1.3 (95% CI: 1.1-1.4), respectively). Fetal intervention also improved survival in some diseases. Echocardiograms were reviewed to group fetuses with similar cardiac physiology and defined categories with high or low/normal cardiothoracic ratio (CTR). Among patients with a high CTR, the cardiovascular profile score was predictive of survival (p=0.009). CONCLUSION: Survival in hydrops depends on the underlying disease, available fetal therapies to resolve hydrops, and the gestational age of delivery and not on the specific anatomic manifestations of hydrops. In hydropic fetuses with high CTRs, the cardiovascular profile score may be a useful prognostic indicator.

Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) represents a spectrum of lung hypoplasia, and consequent pulmonary hypertension (PH) is an important cause of postnatal morbidity and mortality. We studied biomarkers at the maternal-fetal interface to understand factors associated with the persistence of PH. METHODS: Maternal and cord blood samples from fetuses with CDH and unaffected controls were analyzed using a human 39plex immunoassay kit. Cellular trafficking between the mother and the fetus was quantified using quantitative real-time PCR for nonshared alleles. Biomarker profiles were then correlated with CDH severity on the basis of the degree of PH. RESULTS: Cord blood levels of epidermal growth factor, platelet-derived growth factor, and several inflammatory mediators increased significantly as the severity of CDH increased, whereas maternal levels of growth factors and mediators decreased significantly with CDH severity. Maternal cells were increased in fetuses with severe CDH as compared with controls, with elevated levels of the CXC chemokine ligand-10 in patients with the highest trafficking. CONCLUSION: Patients with CDH demonstrate proinflammatory and chemotactic signals in fetal blood at the time of birth. Because some of these molecules have been implicated in the development of PH, prenatal strategies targeting specific molecular pathways may be useful adjuncts to current fetal therapies.

Maternal microchimerism in patients with biliary atresia: Implications for allograft tolerance.

Maternal-fetal cellular trafficking during pregnancy results in bidirectional microchimerism with potentially long-term consequences for the mother and her fetus. Exposure of the fetus to maternal cells results in tolerance to non-inherited maternal antigens (NIMA) and may therefore impact transplant outcomes. We investigated the rates of graft failure and retransplantation after parental liver transplantation in pediatric recipients with biliary atresia (BA), a disease with high levels of maternal microchimerism. We observed significantly lower rates of graft failure and retransplantation in BA recipients of maternal livers compared with BA recipients of paternal livers. Importantly, recipients without BA had equivalent transplant outcomes with maternal and paternal organs, suggesting that increased maternal microchimerism in BA patients may be the underlying etiology for tolerance. These results support the concept that prenatal exposure to NIMA may have consequences for living-related organ transplantation.