PGE₂ Contributes to In vitro MSC‐Mediated Inhibition of Non‐Specific and Antigen‐Specific T Cell Proliferation in MS Patients

Abstract

Current theories of multiple sclerosis (MS) induction and progression place autoreactive T cells in the focus of the pathogenesis. Mesenchymal/stromal stem cells (MSC) have become a promising alternative approach for pathogenic therapy of MS due to their immunomodulatory properties, underlying mechanisms of which are intensive study. The objective of the research was to investigate the contribution of PGE 2 to MSC-mediated suppression in patients with MS using in vitro model of mitogen-and myelin-stimulated T cell cocultivation with autologous/allogeneic MSC. We have showed that PGE 2 production depends on cell-to-cell contact of MSC and lymphocytes. The antigenic stimulation did not affect PGE 2 production following cocultivation of MSC and PBMC, and it is the presence of MSC in cell culture that significantly increases PGE 2 production irrespective of antigenic cultivation conditions. Simultaneously, PGE 2 synthesis correlated with indexes of MSC-mediated suppression of mitogen-and myelinstimulated T cell proliferation in patients with MS. No significant differences in PGE 2 production by autologous and allogeneic MSC have been established. These results have demonstrated that in patients with MS, PGE 2 is one of the possible factors of MSC immunosuppression. The interrelation between PGE 2 concentrations and T cell proliferation suppression mediated by MSC may explain one of the immune mechanisms of cell therapy, which is crucial for the further proper use of MSC in MS research and pathogenic treatment.

Comparability of scalable, automated hMSC culture using manual and automated process steps

“…The increased secretion of PGE-2 by all pre-treated hMSC groups therefore indicates that, regardless of the cell culture process steps utilised, all of the cells demonstrated an immunosuppressive response to an inflammatory microenvironment. Previous experiments have reported a similar magnitude of PGE-2 secretion in mice and human MSCs after alternative pretreatment and co-culture [56,57].…”

Human Mesenchymal Stem Cells Impact Th17 and Th1 Responses Through a Prostaglandin E2 and Myeloid-Dependent Mechanism

“…response [34,35,40,41]. However, PGE2 has also been implicated as part of the mechanisms mediating anti-inflammatory effects of MSCs, including their capacity to limit T-cell proliferation [42], suppress Th17 responses through cell-contact-mediated inhibition [43], induce regulatory T-cell responses [16], and inhibit gd T cells and invariant natural killer T-cell expansion [44].…”

Mesenchymal stromal cells to control donor-specific memory T cells in solid organ transplantation

“…Interestingly, MSCs imposed durable suppression on antigendriven memory T-cell proliferation, which persisted during subsequent cycles of antigen restimulation even though they were no longer present in cocultures [15,36 & ]. Moreover, prostaglandin E 2 (PGE 2 ) concentrations in the supernatants of these cocultures correlated with the index of MSC-mediated suppression of myelin-induced T-cell proliferation [38]. Although MSCmediated immunosuppressive activity is not MHCrestricted, a study using in-vitro cocultures of MSCs and peripheral blood mononuclear cells (PBMCs) of patients with multiple sclerosis revealed that the inhibitory effect of MSCs on myelin-induced memory T-cell proliferation was stronger than that on mitogen-stimulated proliferation [37 & ].…”