Abstract
Treatment with extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) have been suggested as novel therapeutic option in acute inflammation-associated disorders due to their immune-modulatory capacities. As we have previously observed differences in the cytokine profile of independent MSC-EV preparations, functional differences of MSC-EV preparations have to be considered. To evaluate the immune-modulatory capabilities of specific MSC-EV preparations, reliable assays are required to characterize the functionality of MSC-EV preparations prior to administration to a patient. To this end, we established an in vitro assay evaluating the immune-modulatory capacities of MSC-EV preparations. Here, we compared the efficacy of four independent MSC-EV preparations to modulate the induction of T cell differentiation and cytokine production after phorbol 12-myristate 13-acetate (PMA)/Ionomycin stimulation of peripheral blood mononuclear cells (PBMC) derived from six healthy donors. Flow cytometric analyses revealed that the four MSC-EV preparations differentially modulate the expression of surface markers, such as CD45RA, on CD4+ and CD8+ T cells, resulting in shifts in the frequencies of effector and effector memory T cells. Moreover, cytokine profile in T cell subsets was affected in a MSC-EV-specific manner exclusively in CD8+ naïve T cells. Strikingly, hierarchical clustering revealed that the T cell response towards the MSC-EV preparations largely varied among the different PBMC donors. Thus, besides defining functional activity of MSC-EV preparations, it will be crucial to test whether patients intended for treatment with MSC-EV preparations are in principal competent to respond to the envisioned MSC-EV therapy.
Highlights
In a variety of disorders, inflammatory processes are the pathological core, which lead to detrimental effects
In steroid-refractory cases of GvHD the application of mesenchymal stem/stromal cells (MSC) as immune cell therapy options have been evaluated as second-line treatment, with varying results [2]
Our center applied for the first time MSC-Extracellular vesicles (EVs) successfully in a patient with therapy-refractory cutaneous and intestinal acute GvHD IV◦ [9]
Summary
In a variety of disorders, inflammatory processes are the pathological core, which lead to detrimental effects. EVs contain proteins, microRNA, mRNA, and lipids and play an important role in intercellular communication [6,7] Depending on their cellular origin and cytokine cargo with either pro- or anti-inflammatory cytokines, EVs can exert immune-stimulatory or immune-suppressive functions, respectively [8]. The in vivo capability of the patient’s PBMCs to release proinflammatory cytokines was impaired and a decline in proinflammatory cytokines was observed in the blood of the patient during the course of the MSC-EV application. Consistent with these findings, the cutaneous and intestinal GvHD symptoms of the patient improved significantly. It is very likely that the success rate may vary for therapies using MSC-EVs treatment
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