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Sci Transl Med. 2017 Nov 15;9(416). pii: eaam7828. doi: 10.1126/scitranslmed.aam7828.

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

Author information

1
Regenerative Medicine, Division of Cancer Studies and Cancer Research UK King's Health Partners, King's College London, London SE5 9NU, UK.
2
Institute of Pharmaceutical Science, King's College London, London SE1 9NH, UK.
3
Institute of Immunity and Transplantation, University College London, London NW3 2QG, UK.
4
Cancer Institute, University College London, London WC1E 6DD, UK.
5
University Hospital Carl Gustav Carus, 01307 Dresden, Germany.
6
Medical Research Council Centre for Transplantation, King's College London, London SE1 9RT, UK.
7
Centre for Stem Cells and Regenerative Medicine, King's College London, London SE1 9RT, UK.
8
University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK.
9
Bristol Haematology and Oncology Centre, Bristol BS2 8ED, UK.
10
Centre for Haematology, Imperial College London, London W12 0NN, UK.
11
Regenerative Medicine, Division of Cancer Studies and Cancer Research UK King's Health Partners, King's College London, London SE5 9NU, UK. francesco.dazzi@kcl.ac.uk.

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.

PMID:
29141887
DOI:
10.1126/scitranslmed.aam7828
[Indexed for MEDLINE]
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