Low Circulating CD4+ CD25+ Foxp3+ T Regulatory Cell Levels Predict Miscarriage Risk in Newly Pregnant Women with a History of Failure

Abstract

PROBLEM The purpose of this study was to determine whether quantification of peripheral blood Treg cell levels could be used as an indicator of miscarriage risk in newly pregnant women with a history of immunologic reproductive failure. METHOD OF STUDY Fifty-four pregnant women with a history of immunologic infertility and/or pregnancy loss were retrospectively evaluated (mean age: 36.7 ± 4.9 years, 2.8 ± 2.5 previous miscarriages; 1.5 ± 1.9 previous IVF failures). Twenty-three of these women experienced another first trimester miscarriage, and 31 of these women continued their current pregnancies past 12 weeks ('pregnancy success'). The following immunologic parameters were assessed in the first trimester: NK cell 50:1 cytotoxicity, CD56(+) 16(+) CD3(-) (NK), CD56(+) CD3(+) (NKT), TNFα/IL-10, IFNγ/IL-10, CD4(+) CD25(-) Foxp3(+) , total CD4(+) Foxp3(+) (CD4(+ ) CD25(+) Foxp3 plus CD25(- ) Foxp3(+) ), and CD4(+) CD25(+) Foxp3(+) levels. RESULTS Patients with successful ongoing pregnancies experienced a mean (CD4(+) CD25(+) Foxp3(+) ) 'Treg' level of 0.72 ± 0.52%, while those that miscarried in the first trimester experienced a mean Treg level of 0.37 ± 0.29% (P = 0.005). Markers not significantly different between the loss and success groups were NK 50:1 cytotoxicity (P = 0.63), CD56(+) 16(+) 3(+) NK cells (P = 0.63), CD56(+) 3(+) NKT (P = 0.30), TNFα(+) IL-10(+) (P = 0.13), IFNg(+) IL-10(+) (P = 0.63), and CD4(+) 25(-) Foxp3(+) cells (P = 0.10), although total CD4(+) Foxp3(+) levels remained significant (P = 0.02) and CD4(+) 25(+) Foxp3(+) showed the most significant difference (P = 0.005). Mean day of blood draw was 49.2 ± 36.1 days pregnant (median 39.0 days). In addition, patients with a low Treg level (<0.7%) in the first trimester experienced a significantly lower ongoing pregnancy rate than those with a higher Treg level (>0.7%) in the first trimester [44% (15/34) versus 80% (16/20); P = 0.01]. Of the 18 successful pregnancies with sequential Treg results, 85% (11/13) showed a T-regulatory-cell-level increase (mean Treg change 0.33 ± 0.32), while only 40% (2/5) of the failed pregnancies showed a Treg increase (mean Treg change -0.08 ± 0.28; P = 0.02). CONCLUSIONS From these data, we propose that CD4(+) CD25(+) Foxp3(+) T regulatory cells may serve as a superior pregnancy marker for assessing miscarriage risk in newly pregnant women. Larger follow-up studies are needed for confirmation.

Helios-positive functional regulatory T cells are decreased in decidua of miscarriage cases with normal fetal chromosomal content

“…In 2004, Aluvihare et al and our group first reported that Treg cells might mediate maternal tolerance to the fetus in mice and humans (Aluvihare et al, 2004;Sasaki et al, 2004). Since then, many lines of evidence supporting the importance of Treg cells in the implantation period and the early pregnancy period have been presented, with more detailed characterization of Treg cells in mice (Zenclussen et al, 2005(Zenclussen et al, , 2006DarrasseJèze et al, 2006;Kallikourdis et al, 2007;Robertson et al, 2009;Shima et al, 2010;Kahn and Baltimore, 2010;Guerin et al, 2011;Rowe et al, 2011Rowe et al, , 2012Samstein et al, 2012;Yin et al, 2012) and in humans (Tilburgs et al, 2008(Tilburgs et al, , 2009Sasaki et al, 2007;Yang et al, 2008;Jin et al, 2009;Mei et al, 2010;Wang et al, 2010Wang et al, , 2011Winger and Reed, 2011;Lee et al, 2011;Steinborn et al, 2012).…”

Regulatory T Helper Cells in Pregnancy and their Roles in Systemic versus Local Immune Tolerance

“…Recently, it was proposed that low levels of CD25 + FOXP3 + cells could be used to predict miscarriage in women with a history of previous failures. 109 Taken together, data indicate that defects in numbers or function of Treg cells may be involved in the development of RM.…”

Le trophoblaste : chef d’orchestre de la tolérance immunologique maternelle

“…Cette chute des cellules Treg pourrait être impliquée dans le déclenchement du travail puisque qu'elle est moins importante en cas de césarienne programmée [68]. Certains avortements à répétition humains sont associés à des déficits en cellules Treg déciduaux [69] ou circulants [70].…”