Boosting Immune Cell Tolerance May Help Prevent Early Pregnancy Loss

Recurrent pregnancy loss can be devastating and exert a major impact on women, their partners, and society more broadly, but currently there are few options for effective therapies. Over several years, there has been mounting evidence that a deficiency in special immune cells called T-regulatory (Treg) cells, which are essential for preparing the uterus for receptive embryo implantation, are a factor in early pregnancy loss.

A new study in The American Journal of Pathology, published by Elsevier, details evidence in a pre-clinical animal model that boosting these cells improves the chance of healthy pregnancy. The work raises the prospect of evaluating this intervention in women who are prone to experience early pregnancy loss, a common condition affecting natural conception and women undergoing in vitro fertilization (IVF).

Lead investigator Sarah A. Robertson, PhD, The Robinson Research Institute and School of Biomedicine, the University of Adelaide, Australia, explains, "Previous studies have found low numbers of Treg cells in women who experienced early pregnancy loss as well as changes that lead Treg cells to have functional problems that are reminiscent of autoimmune diseases. This can impair the implantation process and suppress development of the early placenta. Therefore, Treg cells provide an attractive target for interventions to improve maternal immune tolerance and protect against pregnancy disorders caused by immune imbalance in at-risk women."

The researchers utilized a mouse model of early pregnancy loss to test a new candidate treatment intervention in which the cytokine interleukin-2 (IL-2) is combined with specific antibodies to target Treg cells. Like humans with recurrent pregnancy loss, the mice have an immune defect that arises at conception and results in later fetal loss.

The researchers administered the IL-2 antibody complex (called IL-2/JES6-1) in the time between conception and embryo implantation to the miscarriage-prone mice and also in mice that have had healthy pregnancies. They observed significant changes to the number and phenotype of the Treg cells in the uterus, blood, and other tissues in both groups of mice. The expanded pool of Treg cells exhibited features that are characteristic of robust pregnancy tolerance and were effective in preventing generation of detrimental effector T cells that threaten pregnancy success. Importantly, the miscarriage-prone mice showed markedly improved pregnancy outcomes after treatment, and their miscarriage rate was consistently reduced from 30% to 11%, which is within the normal range for mice.

Professor Robertson adds, "The results show that efficacy of the IL-2/JES6-1 treatment might be achieved with lower doses, which will likely be important as we consider how to translate the findings to human application. Another notable observation was that treatment in very early pregnancy, even before the embryos commence implantation, has a profound effect on the progression of the pregnancy with lasting benefit into late gestation. This is consistent with growing evidence pointing to embryo implantation and early placental development being the turning point for pregnancy success."

The study demonstrates the potential of targeting Treg cells and provides pivotal evidence to justify human studies; however, it will be important to undertake clinical trials to assemble evidence of safety and benefit in humans before the treatment can be recommended.