Abstract
The immunosuppressive activity of Mesenchymal Stromal Cells (MSCs) is well documented, but the therapeutic benefit is completely unpredictable. Prospective randomized clinical trials remain the only means to address MSC clinical efficacy. However, their success is undermined by the difficulty to stratify patients. Probably the most challenging conundrum is that, despite being immunosuppressive, MSCs are undetectable following administration. Therefore, understanding the fate of infused MSCs could help to shed light on the mechanisms of MSC immunobiology and predict clinical responses.We decided to focus our attention on MSCs used for the treatment of Graft versus Host Disease (GvHD), since there is proof-of-principle of their efficacy.In order to address the mechanisms used by MSCs to deliver immunosuppression we adopted a preclinical model of GvHD by which we demonstrated 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. Importantly, the need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulfed apoptotic MSCs and produce indoleamine 2,3-dioxygenase (IDO) that is ultimately necessary for effecting immunosuppression.
These results point out that crucial events for the delivery of MSC immunosuppressive activity take place soon after infusion. This observation was also supported by the retrospective analysis of the clinical data of a cohort of 60 steroid-resistant acute GvHD patients treated with MSCs, since the assessment of the response as early as 1 week after MSC administration is sufficient for predicting the survival of the patients.
In summary, we propose the innovative concept that response should be assessed early after starting MSC treatments, and patients should be stratified for MSC treatment according to their ability to kill MSCs. Our results strongly suggest the intriguing possibility to treat patients with immune disorders with ex vivo apoptotic MSCs
| Date of Award | 2 May 2019 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Francesco Dazzi (Supervisor) & Martin Bornhauser (Supervisor) |