Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model
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Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model
Reproductive Sciences 1-12 ª The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1933719119828110 journals.sagepub.com/home/rsx
Greene Donald Royster IV, MD1, Justine C. Harris, BS1, Amanda Nelson, MS1, Yessenia Castro, PhD2, R. Patrick Weitzel, PhD3, John Tisdale, MD4, Ryan J. Heitmann, DO5, Alan H. DeCherney, MD1, and Erin F. Wolff, MD1
Abstract There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (Treg) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4þCD25þFoxP3þ Tregs from donors improves litter sizes in DEREG mice with depleted Tregs. Our hypothesis is that DEREG mice treated with a single dose of DT will deplete Tregs and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase Tregs and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of Tregs resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of Tregs at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low Treg. Keywords T regulatory cells, Tregs, rapamycin, recurrent implantation failure, DEREG, murine model, unexplained infertility
Introduction Infertility is present in approximately 7% to 15.5% of all couples in the United States, with unexplained infertility affecting 10% of those couples and recurrent pregnancy loss (RPL) affecting 1% to 3% of all couples.1-3 There are differing opinions and no consensus on the definition of recurrent implantation failure (RIF), but the generally accepted definition is the failure to achieve pregnancy after transferring at least 4 good quality embryos in at least 3 frozen or fresh in vitro fertilization (IVF) or intracytoplasmic sperm injection cycles for patients less than 40 years of age.4-11 Most of these couples do not have an identifiable cause of their implantation failure, making treatment very difficult. Even under the best of conditions, using advanced reproductive technology (ART), only 40% to 60% of euploid, good quality embryos achieve implantation, making endometrial receptivity key to understanding why good quality embryos are unable to achieve implantation.7,11,12 Embryo implantation is an important step in establishi
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