Research ArticleTransplantation

Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation

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Science Translational Medicine  15 Nov 2017:
Vol. 9, Issue 416, eaam7828
DOI: 10.1126/scitranslmed.aam7828

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MSC sacrifice for immunosuppression

Transfer of mesenchymal stromal cells (MSCs) induces immunosuppression, although the cells are undetectable shortly after transfer. The immunosuppressive mechanism of MSCs has been somewhat of a mystery, but Galleu and colleagues now suggest that MSC apoptosis is crucial. They observed in a mouse model of graft-versus-host disease that cytotoxic cells rendered the MSCs apoptotic shortly after transfer. Moreover, cells from patients that responded to MSC therapy had more cytotoxic activity against MSCs. These findings not only provide important mechanistic insight but also suggest that patients could be screened for responsiveness to MSC therapy before transfer.

Abstract

The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.

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