Decreased Adiponectin Levels in Early Pregnancy Are Associated with High Risk of Prematurity for African American Women.

The relationship of low maternal serum adiponectin levels with preterm delivery among a multi-ethnic group has not been extensively investigated. We examined ethnic differences in cytokine/adipokine profiles and whether they contribute to several adverse pregnancy outcomes, particularly preterm delivery. Data and samples were from a large prospective observational cohort (n = 1776) of young, generally healthy pregnant women (African American 36.4%, Hispanic 48.0%, Caucasian 15.6%). Serum cytokine/adipokine concentrations were measured at entry (mean gestational age of 16.83 weeks) using the Liminex xMap Technology. Multivariable analyses were performed. A significant difference in adiponectin level was observed among ethnic groups. African Americans had a decreased adiponectin and increased resistin levels compared to Hispanics and Caucasians (p < 0.05 to p < 0.0001 for each). Decreased adiponectin (lowest quartile) was positively associated with preterm delivery independent of usual risk factors (adjusted odds ratio (AOR) 1.46, 95% confidence interval (CI) 1.05, 2.04 for all preterm and AOR 1.84, 95% CI 1.07, 3.17 for early preterm births). The results were unchanged when women with preeclampsia were excluded. Similar results were observed in African Americans. Decreased adiponectin levels were not related to preterm birth in either Hispanics or Caucasians. Lower adiponectin levels were also significantly associated with an increased risk of developing gestational diabetes (AOR 1.72, 95% CI 1.05, 2.84) and preeclampsia (AOR 1.45, 95% CI 1.00, 2.14) in the whole cohort and in Caucasians. We did not find any consistent relationships between the other markers with outcome variables. Dysregulation in maternal adiponectin at early gestation is associated with an increased risk of preterm delivery. An ethnic difference in adiponectin levels may contribute to a higher preterm delivery rate in African American women.

PHA eludes macrophage suppression to activate CD8+ T cells.

Tumors may include a high proportion of immune modulatory cells and molecules that restrain the anti-cancer response. Activation of T cells to eliminate cancer cells within the immune-suppressive tumor microenvironment remains a challenge. We have shown that C57BL/6 J peritoneal cell culture models features of macrophage-dense tumors as TCR ligation fails to activate T cells unless IFNγ is neutralized or iNOS is inhibited. We tested other forms of T cell activation and found phytohemagglutinin (PHA) distinctive in the ability to markedly expand CD8 T cells in this model. IFNγ or iNOS inhibition was not necessary for this response. PHA triggered less IFNγ production and inhibitory PD-L1 expression than TCR ligation. Macrophages and CD44hi T cells bound PHA. Spleen T cell responses to PHA were markedly enhanced by the addition of peritoneal cells revealing that macrophages enhance T cell expansion. That PHA increases CD8 T cell responses within macrophage-dense culture suggests this mitogen might enhance anti-tumor immunity.

High macrophage PD-L1 expression not responsible for T cell suppression.

Tumors are often comprised of microenvironments (TMEs) with a high proportion of cells and molecules that regulate immunity. Peritoneal cavity (PerC) cell culture reproduces key features of TMEs as lymphocyte proliferation is suppressed by PerC macrophages (Mϕs). We monitored the expression of T cell stimulatory (Class II MHC, B7) and inhibitory (PD-L1) molecules by PerC APCs before and after culture and report here that IFNγ-driven PD-L1 expression increased markedly on PerC Mϕs after TCR ligation, even more so than seen with direct APC activation by LPS. Considering the high APC composition of and pronounced PD-L1 expression by PerC cells, it was surprising that blocking PD-1/PD-L1 interaction by mAb neutralization or genetic ablation did not relieve suppression. This result parallels TME challenges observed in the clinic and validates the need for further study of this culture model to inform strategies to promote anti-tumor immunity.