Induction of acquired fetal tolerance through an EPO-dependent pathway

The National Institute of Allergy and Infectious Diseases awarded The Leland Stanford Junior University $782,736 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research on the induction of acquired fetal tolerance through an erythropoietin-dependent pathway.

The research investigates how T-cell-mediated tolerance is initiated and maintained during human pregnancy, drawing on work examining erythropoietin receptor signaling in conventional type 1 dendritic cells in solid organ transplantation. The hypothesis posits that placental erythropoietin production and trophoblast apoptosis, driven by tissue hypoxia at the maternal-fetal interface, converge to drive fetal antigen-specific regulatory T-cell induction and CD8 T-cell exhaustion through a dendritic cell-dependent mechanism. The research employs primary human tissue, transgenic mouse models, and next-generation spatial biology assays to elucidate these mechanisms. Work includes analysis of dendritic cells, regulatory T-cells, and CD8 T-cells in decidual tissue and uterine draining lymph nodes from healthy pregnancies and women with recurrent pregnancy loss; comparative analysis of human tissue composition and structure against transgenic mouse experimental results; and culture experiments using human dendritic cells and decidual explants with trophoblasts to determine whether the placental secretome alone is sufficient to induce tolerogenic dendritic cell phenotypes.

Performance occurs in Palo Alto, California, with a period of performance extending through August 31, 2031.

Abstract

Acquired tolerance plays a central role across a broad spectrum of human biology spanning organ transplantation and pregnancy. The work proposed here draws inspiration from our work examining epor signaling in conventional type 1 dendritic cells (CDC1S) in solid organ transplantation to understand how t-cell mediated tolerance is initiated and maintained in human pregnancy. Tissue hypoxia at the maternal-fetal interface is a key regulator of placental invasion, spiral artery remodeling, and extracellular matrix remodeling that triggers EPO production by the placenta. Additionally, placental trophoblasts undergo extensive apoptosis throughout gestation. Our hypothesis is that the convergence of placental EPO and trophoblast apoptosis drive fetal AG-specific treg induction and CD8 t-cell exhaustion through a CDC1-dependent mechanism. To test this, we will use a strategy that leverages primary human tissue, animal models, and next-generation assays in spatial biology to understand this process. We will use transgenic mouse models to elucidate the mechanisms by which epor signaling in CDC1S promotes fetal tolerance during successive pregnancies. Using next generation tools for spatial biology, we will analyze CDC1S in human tissue to determine if the composition and structure of decidua and uterine draining lymph nodes align with our proposed model and the results of our transgenic mouse experiments. These results will be compared with samples from women with a history of recurrent pregnancy loss to identify differences in decidual DCS, tregs, and CD8 t-cells that could explain this disorder. Lastly, we will culture human CDC1S and decidual explants with trophoblasts or trophoblast conditioned media (CM) to determine if the placental secretome is sufficient for inducing CDC1 tolerogenic phenotypes. Together, this combination of murine functional models, deep spatial analysis of human tissues, and in vitro studies of human decidua, placenta, and immune cells will allow US to test our model, to assess its relevance in humans, and to provide new directions for treating pregnancy disorders.