Effect of Mesenchymal Stem Cells on Peripheral Immune Cells in Multiple Sclerosis: Results from an International...

The MESEMS trial was a randomized, double-blind, Placebo (Pbo)-controlled, crossover phase 2 study evaluating the safety and efficacy of autologous mesenchymal stromal cells (MSC) in multiple sclerosis (MS). Although the trial did not demonstrate a significant effect on magnetic resonance imaging (MRI) disease activity, MSCs may exert biologically relevant immunomodulatory effects. This ancillary study aimed to characterize peripheral immune changes associated with MSC treatment and to explore whether early immune changes were associated with subsequent clinical or MRI disease activity. Immunophenotyping analyses were performed in two complementary cohorts: a PILOT cohort based on freshly processed blood samples, and a FULL cohort based on cryopreserved peripheral blood mononuclear cells. Longitudinal and short-term treatment effects were assessed using linear mixed-effects models. Exploratory analyses evaluated associations between early immune changes and subsequent relapse or MRI activity. Fifty-one patients were included. Different CD8+ T-cell trajectories in the FULL cohort were observed, with increased CD8+ T cells in MSC-treated patients (P = .032). In short-term analyses (0 to 4 wk), MSC exposure was associated with a relative reduction in CD19+ B cells (MSC-PBO estimate -1.97%; 95% CI -3.43 to -0.50; interaction P = .033) in the PILOT cohort and with increased CD4+ regulatory T cells (interaction P = .006) and Th1/17 cells (interaction P = .028) in the FULL cohort. Exploratory analyses showed that lower early transitional B-cell delta values were associated with subsequent MRI activity in Pbo-treated participants (P = .005). Among participants treated with Pbo, relapses were preceded by decreases in CD8+ T cells (P = .036) and increases in the CD4/CD8 ratio (P = .021), whereas among participants on MSC, relapses were preceded by decreases in CD3+CD56+ T-NK-like cells (P = .035). MSC treatment was associated with short-term immunological changes and with limited longitudinal effects on selected peripheral immune-cell populations, including B cells and regulatory T-cell subsets. Early immune changes were associated with subsequent clinical and radiological disease activity, supporting further investigation of immune biomarkers and mechanisms of MSC-mediated immunomodulation in MS.