Mesenchymal stromal cell therapy to modulate corneal allograft rejection: From bench to bedside

Abstract

AbstractCornea transplantation has been a target for mesenchymal stromal cell (MSC) therapy for several years with a number of publications highlighting the therapeutic potential and mechanism of action of these cells. It is widely known that MSC possess potent anti‐inflammatory capabilities and are able to modulate the activity of a wide array of immune cells including T cells, B cells, dendritic cells and macrophages. This modulation occurs through both cell–cell contact and the paracrine release of soluble factors such as nitric oxide and prostaglandin E2.Although the mechanism of MSC‐mediated immunomodulation following intravenous administration (i.v.) remains to be fully elucidated, it is evident that the lung (where the majority of MSCs become trapped and are subsequently cleared within 24 hours) plays an important role. Our group and others have reported that MSCs enrich innate immune regulatory cells in the lung following i.v. administration.Previous results from our laboratory have demonstrated the efficacy of pre‐transplant infusion of allogeneic (allo) but not autologous (auto) MSC in a fully allogeneic, MHC‐mismatched rat model of cornea transplantation. This suggests that in our previous work the expression of allo‐antigen by allo‐MSCs provides a priming stimulus that enhances their immune modulatory effects while auto‐MSCs administered to an immunologically compatible non‐inflamed (pre‐transplantation) host did not receive the required priming stimulus. We hypothesized that pre‐emptive priming (“licensing”) of auto‐MSC could overcome the lack of efficacy in preventing cornea transplantation rejection by better promoting regulatory innate and adaptive immune cells. We demonstrate that auto‐MSCs administered post‐operatively promote rejection free graft survival upon licensing with a cocktail of pro‐ or anti‐inflammatory cytokines. Interestingly, while the different licensing strategies promote corneal allograft survival in rodents overall, the mechanisms of action appear to be different how these licensed MSC operate in vivo. Finally, the potential of extracellular vesicles secreted from licensed MSC as potential cell‐free therapy will also be discussed.This work contributes to the growing body of literature highlighting the fact that MSC require a pre‐activation stimulus in order to be therapeutically active and the importance of.regulatory cells in mediating MSCs immunomodulatory function.Funding received for this work.This work was supported by Science Foundation Ireland (12/IA/1624), by a grant from the European Commission [FP7 Collaborative Health Project VISICORT (grant number 602470), www.visicort.eu], by infrastructural funds from the European Regional Development Fund and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 814439.Keywords: corneal transplantation, mesenchymal stromal cells, licensing, cytokines, immunomodulation, regulatory cells.