Immunoregulatory effects of placenta-derived decidual stromal cells

Abstract

Decidual stromal cells (DSCs) play a pivotal role in feto-maternal tolerance to prevent rejection of the fetus during pregnancy. This provides a rationale for immunomodulatory stromal cells from the placenta being isolated and used as cellular therapy for inflammatory conditions following hematopoietic stem cell transplantation (HSCT). The term placenta provides a ready source of cells, since this tissue is normally discarded after delivery.

Stromal cells were isolated from different parts of the term placenta, specifically chorionic villi, umbilical cord, and the fetal membranes. DSCs isolated from the fetal membranes had a consistent immunosuppressive capacity in vitro comparable to that of bone marrow-derived mesenchymal stromal cells (MSCs). This immune suppression was partly contact-dependent. Factors of importance in this process were found to include interferon-γ (IFN-γ), prostaglandin E2, indoleamine-2,3-dioxygenase (IDO), and programmed death ligand 1 (PD-L1). In addition, IDO was found to play a role in the DSC-mediated induction of regulatory T cells (Tregs) in vitro. The addition of DSCs to the allogeneic setting in vitro also resulted in a reduction in the concentration of cytokines IFN-γ and interleukin (IL)-17, while the concentrations of IL-10 and IL-2 were elevated. There was also a correlation between increased IL-2 levels and reduced expression of the high-affinity IL-2 receptor on alloantigen-activated T cells. This was consistent with a reduced phosphorylation of STAT5 and reduced uptake of IL-2 in the cultures. The reduced sensitivity to IL-2 was not found to be correlated to an increased exhaustion state, based on expression of programmed death 1 (PD-1) and CD95.

Further characterization of DSCs showed that they have limited differentiation capacity, that they are of maternal origin, and that they have high expression of co-inhibitory markers and integrins that are of importance for migration to inflamed tissue. The expression of these markers was elevated in the presence of external IFN-γ. In contrast, addition of IFN-γ did not increase the antiproliferative effect of DSCs in vitro.

DSCs were expanded to high cell numbers at low passage number. These DSCs were then introduced as a treatment for severe graft-versus-host disease (GVHD), a common complication after HSCT with high mortality rates. In an initial pilot study, nine patients were treated with DSCs. In eight patients who could be evaluated, the overall response rate was 75% and three patients were alive six months after transplant. In a larger patient cohort, immune parameters were monitored up to four weeks after DSC intervention. The patients were divided into two groups, responders and non-responders, depending on GVHD status after DSC treatment. Increased plasma concentrations of IL-6, IL-8, and IP-10 distinctly differentiated the non-responders from the responders before DSC intervention. Although the expression of HLA-DR decreased over time in the CD4+ compartment of the responders, the same group had increasing expression of CCR9 in several cell subsets, including CD4+ T cells, B cells, and monocytes. The responders also had less naïve CD4+ T cells one week after DSC intervention.

Thus, DSCs can be isolated from term placentas and can be expanded to high cell numbers at low passage number. The DSCs have immunomodulatory functions, mediated by several factors. DSCs may be used as a treatment for GVHD, and improvement in GVHD may be distinguished by a specific immune profile.