Lineage-Specific Immune Remodeling Following Autologous Hematopoietic Stem Cell Transplantation in Relapsing-Remitting Multiple Sclerosis

Abstract

Background and ObjectivesAutologous hematopoietic stem cell transplantation (aHSCT) induces durable remission in treatment-refractory relapsing-remitting multiple sclerosis (RRMS). However, to what extent post-transplant immune recovery reflects restoration of pre-treatment state versus selective remodeling remains incompletely understood. We used high-dimensional whole-blood immune profiling to characterize lineage-specific remodeling in patients with RRMS following aHSCT and to compare trajectories with healthy reference profiles. MethodsPeripheral blood from 25 patients with RRMS treated with aHSCT in the RAM-MS trial was analyzed longitudinally at baseline, 100 days, and 6, 12, and 24 months post-transplant. Samples were compared with those from 9 age- and sex-matched healthy controls using a 41-marker mass cytometry panel. Unsupervised clustering and multi-level modeling were used to quantify lineage-level abundance changes and phenotypic remodeling across adaptive and innate compartments. ResultsImmune recovery after aHSCT was characterized by selective and sustained reshaping of specific T-and B-cell subsets rather than uniform restoration of pre-treatment composition. Naive CD4+ and CD8+ T cells gradually repopulated, whereas memory CD4+ T cells remained reduced at 24 months. Memory CD8+ T cells showed a transient early expansion before declining toward baseline levels. Naive B cells expanded early and remained elevated, while memory B cells were durably reduced. B-cell reconstitution involved expansion of activation-associated naive populations alongside contraction of selected memory subsets. Across T-cell compartments, CD161-expressing chemokine receptor-enriched subsets were selectively depleted. Several of these alterations persisted despite partial normalization of overall cell counts. These trajectories were consistent across patients, supporting a robust and reproducible effect of aHSCT on immune architecture. DiscussionaHSCT induces durable, lineage-specific reorganization of adaptive immunity along a shared trajectory across patients, characterized by contraction of inflammatory T-cell programs and hierarchical restructuring of B-cell maturation rather than simple immune restoration.