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 propertiesthat can be of interest in organ transplantation, including expansion of regulatoryT cells (Tregs), a key factor in graft tolerance induction. The immunosuppressionto be associated with MSCs has not yet been defined.Additionally, the impact of the association of everolimus with MSCs on Tregexpansion and on induction of liver graft tolerance has never been studied.The aim of this study was to evaluate the effects of MSCs combined, ornot, 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/withoutsubcutaneous everolimus from D0 to D14. Analysis of circulating Tregs wasperformed at D0, D14 and D28. Secondly, 48 h after LT with a DarkAgouti rat liver, 30 Lewis rats were randomized in 3 groups: everolimus(subcutaneous for 14 days), MSCs (intravenous injection at D2 and D9), orboth everolimus and MSCs. Rejection of the liver graft was assessed byliver tests, histology and survival.Results: Individually, MSC infusion and everolimus promoted Treg expansionin rats, and everolimus had no negative impact on Treg expansionwhen combined with MSCs. However, in the LT model, injections of MSCs2 and 9 days following LT were not effective at preventing acute rejection,and the combination of MSCs with everolimus failed to show any synergisticeffect 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 preventacute rejection, and the association of MSCs with everolimus did not showany synergistic effect.