Abstract :
[en] Mesenchymal stromal cells (MSCs) have potent immunomodulatory and tissue repair properties that make them an attractive tool against graft-vs-host disease (GVHD) and Crohn’s disease.
Despite promising results in phase I/II studies, bone marrow (BM-) derived MSCs have failed to demonstrate their superiority over placebo in two phase III trials. MSCs from different tissue origins display different characteristics, but their therapeutic benefits have never been directly compared in GVHD. In the first part of this work, we compared the impact of BM-, umbilical cord (UC-), and adipose-tissue (AT-) derived MSCs on T-cell function in vitro and assessed their efficacy for the treatment of GVHD induced by injection of human peripheral blood mononuclear cells in NOD-scid IL-2Rnull HLA-A2/HHD mice. In vitro, resting BM- and AT-MSCs were more potent than UC-MSCs to inhibit lymphocyte proliferation, whereas UC- and AT-MSCs induced a higher regulatory T-cell (CD4+CD25+FoxP3+)/T helper 17 ratio. Interestingly, AT-MSCs and UC-MSCs activated the coagulation pathway at a higher level than BM-MSCs. In vivo, AT-MSC infusions were complicated by sudden death in 4 of 16 animals, precluding an analysis of their efficacy. Intravenous MSC infusions (UC- or BM- combined) failed to significantly increase overall survival (OS) in an analysis combining data from 80 mice (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.32–1.08, P = 0.087). In a sensitivity analysis we also compared OS in control vs. each MSC group separately. The results for the BM-MSC vs. control comparison was HR = 0.63 (95% CI 0.30–1.34, P = 0.24) while the figures for the UC-MSC vs. control comparison was HR = 0.56 (95% CI 0.28–1.10, P = 0.09). Altogether, these results suggest that MSCs from various origins have different effects on immune cells in vitro and in vivo. However, none significantly prevented death from GVHD. Finally, our data suggest that the safety profile of AT-MSC and UC-MSC need to be closely monitored given their pro-coagulant activities in vitro.
The safety of MSC therapy in Crohn’s disease has been showed in several studies, but its efficacy and mechanisms of action still need to be investigated. In the second part of this work, we aimed to further assess the safety and efficacy of intravenous injections of allogeneic bone marrow MSCs in Crohn’s disease and to improve the comprehension of their mechanisms of action in order to better design the next phase III trials. Thirteen patients with active refractory Crohn’s disease were enrolled to receive 2 injections of 1.5-2.0x106 MSCs/kg body weight at week 0 and 4. Primary endpoints were safety and clinical response defined by a 100-point decrease in Crohn’s Disease Activity Index (CDAI) at week 8. Secondary endpoints were clinical response, remission (CDAI<150), CDAI, C-reactive protein (CRP) and faecal calprotectin levels at weeks 2, 4, 8 and 12, and incidence of infections by week 12. Ancillary studies included evaluation of immune modulation. At week 8, 2/13 patients achieved clinical response, and CDAI was decreased in 8/10 evaluable patients (mean CDAI decrease of 31.2±80.6). MSC infusions were well tolerated and safe. There were no statistically significant differences between CDAI, CRP levels and faecal calprotectin levels at each time points. We observed a significant increase in the proportions of natural killer (NK) and NKT cells between week 0 and 12. In conclusion, our study provides supplementary data on the safety of systemic infusion of MSCs in luminal Crohn’s disease and guides the following research towards the study of the interactions between NK cells and MSCs.
