Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period

Abstract

Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal-fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.

Keywords: MDSC; infection; intra-amniotic infection; preterm infants; sepsis.

Figure 1

Quantification of granulocytic myeloid‐derived suppressor cells (GR‐MDSC) in cord blood of preterm infants. Mononuclear cells (MNC) were isolated from cord blood (CBMC) of preterm infants, term infants and adults (PBMC). Scatter diagram showing the percentage of GR‐MDSC from total CBMC of preterm and term infants and from total PBMC of adult controls. n = 13–48, **P < 0·01; ***P < 0·001; ****P < 0·0001; Kruskal–Wallis test and Dunn's multiple comparison test.

Figure 2

Quantification of granulocytic myeloid‐derived suppressor cells (GR‐MDSC) in peripheral blood of preterm infants. Mononuclear cells (MNC) were isolated from peripheral blood of preterm infants during the first 3 months of life and from adults. (a) Scatter diagram showing the percentage of GR‐MDSC from total peripheral blood mononuclear cells (PBMC) of preterm infants in the perinatal period days 1–7, the neonatal period days 8–28, the period beyond day 28 and adult controls. n = 13–19, *P < 0·05; **P < 0·01; ****P < 0·0001; n.s. = not significant; Kruskal–Wallis test and Dunn's multiple comparison test. (b) Scatter diagram showing the percentage of GR‐MDSC from total PBMC of preterm infants depending on postnatal age. Regression line shows correlation between percentages of GR‐MDSC and postnatal age. n = 51; ****P < 0·0001; Spearman's correlation.

Figure 3

Quantification of granulocytic myeloid‐derived suppressor cells (GR‐MDSC) in preterm infants with intra‐amniotic infection (IAI) or neonatal sepsis. Mononuclear cells (MNC) were isolated from cord (CBMC) or peripheral blood (PBMC) of preterm infants. (a) Scatter diagram showing the percentage of GR‐MDSC from total CBMC of preterm infants without IAI (no IAI) or with IAI (IAI). n = 12–59; **P < 0·01; Mann–Whitney test. (b) Scatter diagram showing the percentage of GR‐MDSC from total PBMC of preterm infants without infection (no infection) or with postnatal sepsis (neonatal sepsis). n = 10–51; *** P < 0·001; Mann–Whitney test.

Figure 4

Quantification of granulocytic myeloid‐derived suppressor cells (GR‐MDSC) in dependence of inflammatory markers C‐reactive protein (CRP) and white blood cell counts (WBC). Mononuclear cells (MNC) were isolated from peripheral blood (PBMC) of preterm infants and CRP and white blood cell counts were measured as part of routine laboratory evaluation. (a) Scatter diagram showing the percentage of GR‐MDSC from total PBMC of preterm infants with normal (CRP < 1·0 mg/dl) and elevated CRP (CRP > 1·0 mg/dl). n = 36–89; ***P < 0·001. Mann–Whitney test. (b) Scatter diagram showing the percentage of GR‐MDSC from total PBMC of preterm infants depending on white blood cell count. Regression line shows correlation between percentages of GR‐MDSC and white blood cell count. n = 206; ****P < 0·0001, Spearman's correlation.