Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial

Abstract

BackgroundRIF is clinically defined as the failure of good quality embryos to implant into the uterus following at least three cycles of In Vitro Fertilization/Embryo Transfer (IVF/ET). During human pregnancy, a genetically different fetus is allowed to survive within the uterus despite the maternal recognition of fetal alloantigens. Compared with normal pregnant women, early loss of embryo is associated with systemic lower levels of Treg cells in IVF. Moreover, several lines of evidence have indicated that differentiation of naive T cells into Th17 is deleterious for normal pregnancy and may cause implantation failure. Sirolimus as the most common mTOR (mammalian target of Rapamycin) inhibitor is able to effectively prevent allograft rejection. Here we aimed to evaluate Sirolimus effects on Th17/Treg axis and subsequently on pregnancy outcome. Methods and materials121 patients with a history of at least 3 implatation failures were selected and enrolled in this clinical trial. Blood was drawn between days 5 and 10 of the cycle prior to the index IVF/ET cycle to assess baseline value of Th17 cells and regulatory T cells ratios using flowcytometry. A Th17/Treg cell ratio equal or >0.74 was considered to be the elevated Th17/Treg cell ratio. In 76 patients with elevated Th17/Treg ratios, 43 individuals were treated with Sirolimus and 33 remained untreated. ResultsOur results demonstrated that Sirolimus treatment led to an increase in Treg cells number and function in treated group and reduced the frequency and function of Th17 cells. Moreover Th17/Treg cell ratio, significantly reduced from 1.18 ± 0.46% to 0.9 ± 0.45% following Sirolimus intervention (P = 0.024). In contrast, no significant difference in Th17 and Treg cell frequencies and Th17/Treg cell ratio was observed in untreated control subjects before and after ET. Finally our data showed a significantly higher clinical pregnancy rate (55.81%) in Sirolimus-treated patients compared with control group (24.24%) (P < 0.0005). We also found a significantly increased live birth rate (48.83%) in RIF women who received Sirolimus compared with control group (21.21%) (P < 0.0001). ConclusionThe findings of the current study revealed the fact that Sirolimus exhibit potent immunosuppressive effects by blocking intracellular immune responses downstream of co-stimulatory signals, also is able to improve reproductive outcome in RIF women with imbalanced Th17/Treg ratio by modulate of Th17 /Treg axis, thus representing a new approach for the potential treatment of patients with embryo implantation failure.