Mesenchymal stromal cells combined with everolimus promote Treg expansion but do not synergize in a rat liver transplant rejection model

Background: Mesenchymal stromal cells (MSCs) have particular properties
that can be of interest in organ transplantation, including expansion of regulatory
T cells (Tregs), a key factor in graft tolerance induction. The immunosuppression
to be associated with MSCs has not yet been defined.
Additionally, the impact of the association of everolimus with MSCs on Treg
expansion and on induction of liver graft tolerance has never been studied.
The aim of this study was to evaluate the effects of MSCs combined, or
not, with everolimus, on Treg expansion and in a model of liver transplantation
(LT) rejection in the rat.
Methods: Firstly, Lewis rats received intravenous MSCs at D9 with/without
subcutaneous everolimus from D0 to D14. Analysis of circulating Tregs was
performed at D0, D14 and D28. Secondly, 48 h after LT with a Dark
Agouti rat liver, 30 Lewis rats were randomized in 3 groups: everolimus
(subcutaneous for 14 days), MSCs (intravenous injection at D2 and D9), or
both everolimus and MSCs. Rejection of the liver graft was assessed by
liver tests, histology and survival.
Results: Individually, MSC infusion and everolimus promoted Treg expansion
in rats, and everolimus had no negative impact on Treg expansion
when combined with MSCs. However, in the LT model, injections of MSCs
2 and 9 days following LT were not effective at preventing acute rejection,
and the combination of MSCs with everolimus failed to show any synergistic
effect when compared to everolimus alone.
Conclusion: Everolimus may be used in association with MSCs. However,
in our model of LT in the rat, post-transplant MSC injections did not prevent
acute rejection, and the association of MSCs with everolimus did not show
any synergistic effect.