Regulatory B Cells Contribute to the Clinical Response After Bone Marrow-Derived Mesenchymal Stromal Cell Infusion in Patients With Systemic Sclerosis

• Published in: Stem cells translational medicine Vol. 12; no. 4; pp. 194 - 206
• Main Authors: Loisel, Séverine, Lansiaux, Pauline, Rossille, Delphine, Ménard, Cédric, Dulong, Joëlle, Monvoisin, Céline, Bescher, Nadège, Bézier, Isabelle, Latour, Maëlle, Cras, Audrey, Farge, Dominique, Tarte, Karin
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 17.04.2023; Wiley
• Subjects: B-Lymphocytes, Regulatory; Bone Marrow; Cytokines - metabolism; Human Clinical; Humans; Interleukin-10 - metabolism; Life Sciences; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - therapy; clinical trial; systemic sclerosis; immune monitoring; Breg; mesenchymal stromal cells
• ISSN: 2157-6564; 2157-6580; 2157-6580
• DOI: 10.1093/stcltm/szad010

Abstract Mesenchymal stromal cells (MSCs) have recently emerged as an interesting therapeutic approach for patients with progressive systemic sclerosis (SSc), a rare and life-threatening orphan autoimmune disease. Whereas MSC immunomodulatory potential is considered as a central mechanism for their clinical benefit, very few data are available on the impact of MSCs on immune cell subsets in vivo. In the current extended study of a phase I/II clinical trial exploring the injection of a single dose of allogeneic bone marrow-MSCs (alloBM-MSCs) in patients with severe SSc (NCT02213705), we performed a longitudinal in-depth characterization of circulating immune cells in 19 MSC-treated patients, including 14 responders and 5 non-responders. By a combination of flow cytometry and transcriptomic analyses, we highlighted an increase in circulating CD24hiCD27posCD38lo/neg memory B cells, the main IL-10-producing regulatory B cell (Breg) subset, and an upregulation of IL10 expression in ex-vivo purified B cells, specifically in responder patients, early after the alloBM-MSC infusion. In addition, a deeper alteration of the B-cell compartment before alloBM-MSC treatment, including a higher expression of profibrotic cytokines IL6 and TGFβ by sorted B cells was associated with a non-responder clinical status. Finally, BM-MSCs were able to directly upregulate IL-10 production in activated B cells in vitro. These data suggest that cytokine-producing B cells, in particular Breg, are pivotal effectors of BM-MSC therapeutic activity in SSc. Their quantification as activity biomarkers in MSC potency assays and patient selection criteria may be considered to reach optimal clinical benefit when designing MSC-based clinical trials. Graphical Abstract Graphical Abstract