Abstract :
[en] Liver transplantation (LTx) is presently considered as the most effective treatment for the majority of end-stage liver diseases, with highly favorable results in both the short- and long-term. However, the long-term use of immunosuppressive drugs (ISDs) exposes liver transplant recipient (LTR) to numerous side effects that restrict these excellent outcomes. Furthermore, the use of marginal livers to address the shortage of liver grafts exposes the recipient to more complications, primarily due to ischemia-reperfusion injuries (IRI). Many strategies, aiming at preventing and attenuating IRI in the liver and limiting the use of ISD and their linked side-effects, are studied. Mesenchymal stromal cells (MSCs), thanks to their immunosuppressive properties including their beneficial effect on regulatory T cells (Treg), could have the potential to modulate immunity to prevent acute rejection (AR) after LTx without (or with lower doses of) ISDs as well as to reduce IRI. In addition to very encouraging preclinical results, the safety and efficacy of MSC therapy in human subjects require additional validation before being expanded for broader use in large-scale LTx programs. Furthermore, many parameters about the use of MSCs including the optimal ISDs to combine with MSCs in order to achieve a synergistic effect, still need to be defined. Here, we report on the first prospective phase I-II controlled clinical trial investigating the safety and tolerability of a single allogeneic bone marrow-derived MSC injection following deceased donor LTx in addition to conventional ISD regimen. No potential adverse effect related to MSC treatment was observed, particularly there was no increase in the rate of opportunistic complications which were comparable in both the MSC and control groups. Nevertheless, our data suggest that MSC may promote the emergence of donor-specific antibodies (DSAs) against liver or MSC donors, encouraging the monitoring of DSA in future studies. Moving from bed to bench-side, we showed, in vivo, that MSC and the association of everolimus and MSC could be beneficial for regulatory Treg expansion. However, in our LTx model in rat, 2 MSC injections after LTx were inefficient in preventing severe AR. Additionally, when compared to everolimus alone, there was no difference in the effects of the association of MSCs with everolimus. One of our hypotheses is that MSCs should be injected earlier.
As a whole, our work brings new data supporting the use of MSC for LTx. Further investigations on MSCs in LTx will probably help to design more efficient (pre)clinical studies.
