Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 416, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aam7828
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Funding
- Bloodwise Specialist Programme [14019, 12006]
- Bloodwise Clinical Research Training Fellowship [15029]
- MRC [MC_PC_14105, MC_G0802523, MR/L022699/1] Funding Source: UKRI
- British Heart Foundation [RG/13/12/30395] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [20265] Funding Source: researchfish
- Medical Research Council [MR/J006742/1, MC_G0802523, MC_PC_14105, MR/L022699/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10275] Funding Source: researchfish
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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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