Neuroprotection and Immunomodulation With Mesenchymal Stem Cells in Chronic Experimental Autoimmune Encephalomyelitis

Kassis, Ibrahim; Grigoriadis, Nikolaos; Gowda-Kurkalli, Basan; Mizrachi-Kol, Rachel; Ben‐Hur, Tamir; Slavin, Shimon; Abramsky, Oded; Karussis, Dimitrios

doi:10.1001/archneur.65.6.753

Cited by 317 publications

(285 citation statements)

References 32 publications

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“…BMSC exhibited powerful immunomodulatory effects in various conditions in vivo. Specifically, intravenously injected BMSC effectively attenuated EAE [193,194], resulting in efficient protection of the CNS from tissue injury [195].…”

Section: Therapeutic Plasticity Of Non-neural Stem Cellsmentioning

confidence: 99%

“…Therefore, intravenously administered BMSCs may arrive at the site of active disease in the inflamed CNS [194]. Alternatively, BMSCs can be delivered into the ventricular and subarachnoid space from which they inhibit EAE [195]. Several studies addressed the issue of BMSC migration within CNS tissue [280,281], but it is not yet clear whether this occurs efficiently in EAE.…”

Section: Route Of Cell Deliverymentioning

confidence: 99%

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Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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Section: Therapeutic Plasticity Of Non-neural Stem Cellsmentioning

confidence: 99%

Section: Route Of Cell Deliverymentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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“…Recently, reports have appeared suggesting that bone marrow-derived cells can ameliorate toxic and inflammatory experimental demyelinating disease following intravenous delivery [1,3,5,7,[13][14][15][16]. However, whether this effect is achieved through cell replacement and…”

Section: Mesenchymal Stem Cells; Multiple Sclerosis; Experimental Allmentioning

confidence: 99%

“…Others have previously reported the amelioration of EAE using bone marrow derived cells [1,3,5,7,[13][14][15][16]. Some studies propose and indeed help define systemic immune effects [3,5,7,13,14]; some find there to be CNS infiltration (following intravenous delivery of cells) [1,3,5,16] with certain groups proposing not immune 'therapeutic' activity but rather differentiation into microglia and/or oligodendrocyte lineage cells [1,5,16].…”

mentioning

confidence: 99%

“…Some studies propose and indeed help define systemic immune effects [3,5,7,13,14]; some find there to be CNS infiltration (following intravenous delivery of cells) [1,3,5,16] with certain groups proposing not immune 'therapeutic' activity but rather differentiation into microglia and/or oligodendrocyte lineage cells [1,5,16]. Alternatively, local neuroprotective effects dependent on local infiltration also have been suggested as the therapeutic mechanism [5,16]. Any and all of these possible activities could of course be therapeutically relevant to MS [16], but whether one or other are more important functionally is a vital question if any cell therapy paradigm is to be optimised.…”

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Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration

Gordon

Pavlovska

Glover³

et al. 2008

Neuroscience Letters

113

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Multiple sclerosis is a currently incurable inflammatory demyelinating syndrome. Recent reports suggest that bone marrow derived mesenchymal stem cells may have therapeutic potential in experimental models of demyelinating disease, but various alternative mechanisms, ranging from systemic immune effects to local cell replacement, have been proposed. Here we used intraperitoneal delivery of human mesenchymal stem cells to help test (a) whether human cells can indeed suppress disease, and (b) whether CNS infiltration is required for any beneficial effect. We found pronounced amelioration of clinical disease but profoundly little CNS infiltration. Our findings therefore help confirm the therapeutic potential of mesenchymal stem cells, show that this does indeed extend to human cells, and are consistent with a peripheral or systemic immune effect of human MSCs in this model. Keywords Mesenchymal stem cells; Multiple sclerosis; Experimental allergic encephalomyelitisMultiple sclerosis is an acquired inflammatory demyelinating syndrome of unknown cause, and which is currently incurable. In many individuals, progressive disability occurs during the course of the disease, as a consequence of irreversible CNS damage. The ineffectiveness of current therapies has emphasised the importance of novel treatment approaches, and stem cells are widely held as having particular promise.Bone marrow derived mesenchymal stem cells can proliferate substantially, and can differentiate into cells of all three germ cell layers, including neural cells; moreover they are relatively accessible, could be used for autologous therapy, and are capable of entering the CNS (particularly when damaged) from the circulation [6,11]. They are therefore considered good candidates for early clinical stem cell therapeutic studies.Recently, reports have appeared suggesting that bone marrow-derived cells can ameliorate toxic and inflammatory experimental demyelinating disease following intravenous delivery [1,3,5,7,[13][14][15][16]. However, whether this effect is achieved through cell replacement and

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Safety and Immunological Effects of Mesenchymal Stem Cell Transplantation in Patients With Multiple Sclerosis and Amyotrophic Lateral Sclerosis

Karussis¹,

Karageorgiou²,

et al. 2010

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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 63.2ϫ 10 6(2.5ϫ10 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 (Յ25 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 ϩ CD25 ϩ regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40 ϩ , CD83 ϩ , CD86 ϩ , 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.

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Neuroprotection and Immunomodulation With Mesenchymal Stem Cells in Chronic Experimental Autoimmune Encephalomyelitis

Cited by 317 publications

References 32 publications

Cell Therapy for Multiple Sclerosis

Cell Therapy for Multiple Sclerosis

Human mesenchymal stem cells abrogate experimental allergic encephalomyelitis after intraperitoneal injection, and with sparse CNS infiltration

Safety and Immunological Effects of Mesenchymal Stem Cell Transplantation in Patients With Multiple Sclerosis and Amyotrophic Lateral Sclerosis

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