Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis

Abstract

Objective: To evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous mesenchymal stem cells (MSCs) (also called mesenchymal stromal cells) in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).

Design: A phase 1/2 open-safety clinical trial. Patients Fifteen patients with MS (mean [SD] Expanded Disability Status Scale [EDSS] score, 6.7 [1.0]) and 19 with ALS (mean [SD] Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS] score, 20.8 [8.0]) were enrolled. Intervention After culture, a mean (SD) of 63.2 × 10(6) (2.5 × 10(6)) MSCs was injected intrathecally (n = 34) and intravenously (n = 14). In 9 cases, MSCs were magnetically labeled with the superparamagnetic iron oxide ferumoxides (Feridex).

Main outcome measures: The main outcome measure was the recording of side effects. Follow-up (≤25 months) included adverse events evaluation, neurological disability assessment by means of the EDSS, magnetic resonance imaging to exclude unexpected pathologies and track the labeled stem cells, and immunological tests to assess the short-term immunomodulatory effects of MSC transplantation.

Results: Twenty-one patients had injection-related adverse effects consisting of transient fever, and 15 reported headache. No major adverse effects were reported during follow-up. The mean ALSFRS score remained stable during the first 6 months of observation, whereas the mean (SD) EDSS score improved from 6.7 (1.0) to 5.9 (1.6). Magnetic resonance imaging visualized the MSCs in the occipital horns of the ventricles, indicating the possible migration of ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord. Immunological analysis revealed an increase in the proportion of CD4(+)CD25(+) regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40(+), CD83(+), CD86(+), and HLA-DR on myeloid dendritic cells at 24 hours after MSC transplantation.

Conclusion: Transplantation of MSCs in patients with MS and ALS is a clinically feasible and relatively safe procedure and induces immediate immunomodulatory effects. Trial Registration clinicaltrials.gov Identifier: NCT00781872.

Figure 1

Clinical follow-up of patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) after transplantation of mesenchymal stem cells (MSCs). A, The Expanded Disability Status Scale (EDSS) score in patients with MS was significantly reduced at 1 (P<.001), 3 (P<.001), and 6 (P=.001) months, compared with baseline (2-tailed paired t test). B, Changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) score were not statistically significant.

Figure 2

Magnetic resonance imaging after injection of ferumoxides-labeled mesenchymal stem cells. A, An axial T2-weighted gradient echo scan through the inferior thoracic cord shows a hypointense pial signal coating the cord similar to that of superficial siderosis, characteristic of ferumoxides (Feridex)-labeled cells. B, Axial T2-weighted gradient echo scan through the cervical cord shows hypointensity of the dorsal roots and their entry zone and a similar hypointensity of the ventral root entry zones, suggesting the presence of ferumoxides-labeled cells.

Figure 3

A 3-T diffusion-weighted axial magnetic resonance imaging scan of the brain shows hyperintense signals in the occipital horns of the brain ventricles, indicating the presence of dependent transplanted cells that were not magnetically labeled.

Figure 4

Immunological effects in patients with multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) injected intravenously and intrathecally with mesenchymal stem cells (MSCs). Peripheral blood monocytes were obtained from 12 patients (7 with MS and 5 with ALS, combined as a single group) at baseline and at 4 and 24 hours after autologous MSC transplantation. A, Mean (SD) changes in the proportions of CD4⁺ CD25⁺ and CD40⁺ lymphocytes and of CD83⁺, CD86⁺, and HLA-DR⁺ myeloid dendritic cells (fluorescence-activated cell sorter analysis), at 4 and 24 hours after MSC transplantation. *Statistically significant changes (P<.05) compared with baseline (2-tailed paired t test). B, Changes in lymphocytic proliferation on stimulation with phytohemagglutinin after MSC transplantation (tested by means of tritiated thymidine uptake of peripheral blood lymphocytes obtained from MSC-treated patients with ALS and with MS that were then stimulated with phytohemagglutinin), at 4 and 24 hours after MSC transplantation. The differences were statistically significant (P=.001) compared with baseline (2-tailed paired t test).