Administration of CD4+CD25highCD127-FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study

BioDrugs. 2021 Jan;35(1):47-60. doi: 10.1007/s40259-020-00462-7. Epub 2021 Jan 5.


Background: Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (Tconv) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4+CD25highCD127-FoxP3+ T regulatory (Treg) cells may inhibit this destruction through suppressive activity exerted on Tconv cells.

Methods: We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous Treg cells for relapsing-remitting MS. The patients received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 106 Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 106 Treg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up.

Results: No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of Treg cells or Tconv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(-) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group.

Conclusions: No serious adverse events were reported in the 14 patients with MS treated with Treg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety.

Trial registration: EudraCT: 2014-004320-22; registered 18 November 2014.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Forkhead Transcription Factors
  • Humans
  • Multiple Sclerosis*
  • Multiple Sclerosis, Relapsing-Remitting* / drug therapy
  • Quality of Life
  • Recurrence
  • T-Lymphocytes, Regulatory


  • FOXP3 protein, human
  • Forkhead Transcription Factors