AUTHOR=Müller Malin , Pavlovic Ivan , Wiberg Anna , Burman Joachim 

TITLE=Longitudinal immune profiling following autologous hematopoietic stem cell transplantation in multiple sclerosis: insights into immune reconstitution and disease modulation

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1601223

DOI=10.3389/fimmu.2025.1601223

ISSN=1664-3224

ABSTRACT=IntroductionAutologous hematopoietic stem cell transplantation (AHSCT) is an effective treatment for relapsing remitting multiple sclerosis, yet the mechanisms underlying immune reset and sustained remission remain incompletely understood. This study provides a longitudinal immune profiling of patients undergoing AHSCT, with a specific focus on immune reconstitution at two years post-AHSCT.MethodsPeripheral blood mononuclear cells (PBMCs) were collected from 22 relapsing-remitting multiple sclerosis patients at baseline and multiple time points post-AHSCT. Immune reconstitution was characterized using high-dimensional mass cytometry (CyTOF) and flow cytometry to assess phenotypic changes in B cells, T cells, and myeloid cells.ResultsAHSCT led to profound alterations in immune cell populations. B-cell recovery was marked by a rapid expansion of naïve B cells, while memory B cells and plasmablasts remained depleted. Notably, patients with evidence of inflammatory disease activity (EIDA) post-AHSCT exhibited higher pre-transplant frequencies of non-switched IgD+IgM+ memory B cells, raising the possibility of a potential biomarker for treatment response. Myeloid-cell reconstitution showed a decline in classical monocytes and an increase in non-classical monocytes and plasmacytoid dendritic cells, potentially shifting the immune balance toward a more tolerogenic state. CD4 T-cell reconstitution demonstrated a shift from central memory (Tcm) to effector memory (Tem) phenotypes, with a selective depletion of polyfunctional Th1/Th17cells lacking PD-1 expression. Clusters enriched for PD-1+ Tem CD4 T cells appeared to differ between patients with and without EIDA. Furthermore, an increase in atypical naïve CCR7⁻CD62L⁻ CD4 T cells was observed in EIDA patients, raising questions about their role in the pathophysiology of MS. CD8 T-cell reconstitution followed a similar pattern, with a shift from a naïve/Tcm-dominant to a Tem-skewed population, albeit with substantial interpatient variability. Mucosal-associated invariant T cells (MAIT) cells showed a sustained decrease, possibly reflecting microbiota alterations post-transplant.ConclusionsTaken together, these findings provide an exploratory characterization of immune reconstitution following AHSCT, highlighting candidate biomarkers and mechanisms that warrant validation in larger cohorts to guide patient stratification and monitor treatment responses in multiple sclerosis.