Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

Dutton, L C; Dudhia, J; Catchpole, B; Hodhkiss-Geere, H; Werling, D; Connolly, D J

Abstract

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due
to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2
under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the
EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2.

Citation

Dutton, L. C., Dudhia, J., Catchpole, B., Hodhkiss-Geere, H., Werling, D., & Connolly, D. J. (in press). Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor. https://doi.org/10.1038/s41598-018-31569-1

• Journal Article Type: Article
• Acceptance Date: Aug 7, 2018
• Deposit Date: Aug 29, 2018
• Publicly Available Date: Aug 29, 2018
• Journal: Scientific Reports (Nature)
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 13351
• DOI: https://doi.org/10.1038/s41598-018-31569-1
• Public URL: https://rvc-repository.worktribe.com/output/1386291