Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation - PubMed (original) (raw)

. 2017 Nov 15;9(416):eaam7828.

doi: 10.1126/scitranslmed.aam7828.

Yanira Riffo-Vasquez 2, Cristina Trento 1, Cara Lomas 3 4, Luigi Dolcetti 1, Tik Shing Cheung 1, Malte von Bonin 5, Laura Barbieri 1, Krishma Halai 1, Sophie Ward 3 4, Ling Weng 1, Ronjon Chakraverty 3 4, Giovanna Lombardi 6, Fiona M Watt 7, Kim Orchard 8, David I Marks 9, Jane Apperley 10, Martin Bornhauser 1 5, Henning Walczak 4, Clare Bennett 3 4, Francesco Dazzi 11 10

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

Antonio Galleu et al. Sci Transl Med. 2017.

Free article

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.

Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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