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 opens in new tab/window in The American Journal of Pathology opens in new tab/window, 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.

Notes for editors

The article is “IL-2 Complexed with Anti—IL-2 Expands the Maternal T-Regulatory Cell Pool and Alleviates Fetal Loss in Abortion-Prone Mice,” by Kerrie L. Foyle, PhD, Peck Y. Chin, PhD, Carsten Merkwirth, PhD, Jasmine Wilson, PhD, Shanna L. Hosking, BSc, Ella S. Green, PhD, Mei Y. Chong, BSc, Bihong Zhang, PhD, Lachlan M. Moldenhauer, PhD, Greg D. Ferguson, PhD, Gerald P. Morris, MD, PhD, James G. Karras, PhD, Alison S. Care, PhD, and Sarah A. Robertson, PhD (https://doi.org/10.1016/j.ajpath.2024.07.012 opens in new tab/window). It appears in The American Journal of Pathology, volume 194, issue 11 (November 2024), published by Elsevier.

The article is openly available for 30 days at https://ajp.amjpathol.org/article/S0002-9440(24)00283-9/fulltext opens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors contact Professor Sarah A. Robertson, PhD, NHMRC Investigator Fellow, The University of Adelaide, at +61 (0) 402 856 695; [email protected] opens in new tab/window, or Rhiannon Koch, Media Officer, University of Adelaide, at +61 (0)481 619 997, or [email protected] opens in new tab/window.

The study was supported by the National Health and Medical Research Council project grant APP1041335; Ferring Research Institute Inc. research study agreement UA 5.05.17; and National Heart Foundation of Australia Future Leader Fellowship 101998.

About The American Journal of Pathology

The American Journal of Pathology opens in new tab/window, official journal of the American Society for Investigative Pathology opens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. https://ajp.amjpathol.org opens in new tab/window

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