The favorable outcome of umbilical cord blood transplantation (UCBT) is compromised by prolonged time to engraftment, delayed immunologic reconstitution and late memory T cell skewing. Zebrafish and mouse studies have shown that transient ex vivo prostaglandin E2 (PGE2) exposure increases HSC number, homing and engraftment in vivo. We performed a Phase Ib clinical trial of double UCBT (dUCBT), using one untreated and one ex vivo PGE2-treated UCB unit, to determine safety and engraftment parameters. We demonstrated a significant reduction in the median time to myeloid engraftment compared with historic controls, and PGE2- derived hematopoiesis. We determined, that short exposure to PGE2 induced stabilization of b-catenin in UCB T cells and dendritic cells (DCs). In UCB T cells PGE2 modified the Wnt signaling cascade through EP2/EP4 receptors and cAMP-mediated phosphorylation of Gsk3, resulting in stabilization of ?-catenin and TCF-mediated transcription. PGE2 induced Wnt target genes, including components of the Wnt pathway but also Wnt receptors, suggesting that ex vivo PGE2 treatment primes T cells for Wnt/?-catenin signaling in vivo. Wnt/?-catenin signaling in mice has been demonstrated to promote the generation of highly potent stem cell memory CD8+ T cells. Consistent with our hypothesis, we found that T cells in PGE2-UCBT recipients displayed limited in vivo expansion, increase in CD62+ cell fraction in the CD8+ population and molecular features of central memory-like cells characterized by increased expression of transcription factors TCF7 and EOMES and low levels of KLRG, all of which are regulated by Wnt signaling. Furthermore, compared to control dUCBT recipients, PGE2-UCBT recipients had improved quantitative and qualitative thymic reconstitution as determined by TREC values and by immunoSEQ assay. These patients displayed potent antiviral immunity and reduced incidence of CMV and EBV viremia. These outcomes are of particular importance in allogeneic HSCT and specifically UCBT where delayed immune reconstitution is characterized by late memory T cell skewing and prolonged impairment of thymic function. Our clinical and laboratory findings suggest that the engrafting advantage of PGE2-treated HSC might allow for the use of a single UCB unit in adult patients, and that PGE2 might alter reconstitution of the innate and adaptive immunity by priming immune cells for Wnt mediated signaling in vivo. To these ends we will undertake the following studies to: 1) Determine the clinical outcome of single ex vivo PGE2 incubated UCB unit transplantation. 2) Examine the effect ex vivo PGE2 incubation of the UCB on the differentiation, polarization and function of T cells. 3) Examine the effects of ex vivo PGE2 incubation of the UCB on the molecular and functional properties of DC.
Our proposal will test the hypothesis that PGE2 pre-incubation of the stem cell graft provides a novel approach to accelerate HSC engraftment and to improve immunity by altering the properties and functions of T cells and DC. If these studies are successful, they will have major implications on the outcome of UCBT, in which delayed engraftment and impairment of immunity are serious causes of morbidity and mortality and compromise quality of life.
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