Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression

Einstein, Ofira; Fainstein, Nina; Vaknin, Ilan; Mizrachi-Kol, Rachel; Reihartz, Etti; Grigoriadis, Nikolaos; Lavon, Iris; Baniyash, Michal; Lassmann, Hans; Ben‐Hur, Tamir

doi:10.1002/ana.21033

Cited by 236 publications

(271 citation statements)

References 37 publications

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“…Peripheral immune modulation has also been observed following systemic MSC and NPC transplantation in EAE, owing to a remarkable accumulation of transplanted cells at the level of secondary lymphoid organs, where T-cell proliferation and production of proinflammatory cytokines were inhibited (Einstein et al, 2007;Pluchino et al, 2009b;Zappia et al, 2005). Furthermore, exclusive targeting of the peripheral immune system has been reported in relapsing EAE in mice after subcutaneous NPC injection (Pluchino et al, 2009b).…”

Section: Signaling At a Distance (Endocrine)mentioning

confidence: 99%

How stem cells speak with host immune cells in inflammatory brain diseases

Pluchino

Cossetti

2013

Glia

111

109

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Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.

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Section: Signaling At a Distance (Endocrine)mentioning

confidence: 99%

How stem cells speak with host immune cells in inflammatory brain diseases

Pluchino

Cossetti

2013

Glia

111

109

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“…Following systemic delivery, immune regulation by NPCs occurs in secondary lymphoid organs, such as the lymph nodes [177] or the spleen [178].…”

Section: Immune Modulationmentioning

confidence: 99%

“…One school of thought was suggested that NPCs induce apoptosis of Th1 cells, but not Th2 cells, selectively, via the inflammationdriven up-regulation of membrane expression of functional death receptor ligands (e.g., Fas Ligand, TNF-related apoptosis-inducing ligand-TRAIL, Apo3 ligand) on NPCs [173]. Alternatively, it has been suggested that NPCs inhibit T-cell activation and proliferation by a nonspecific, bystander immune suppressive action [177]. This notion emerged from co-culture experiments that showed a striking inhibition of the activation and proliferation of EAE-derived, as well as naive, T cells by NPCs, following stimulation by various stimuli [171,177,179].…”

Section: Immune Modulationmentioning

confidence: 99%

“…Alternatively, it has been suggested that NPCs inhibit T-cell activation and proliferation by a nonspecific, bystander immune suppressive action [177]. This notion emerged from co-culture experiments that showed a striking inhibition of the activation and proliferation of EAE-derived, as well as naive, T cells by NPCs, following stimulation by various stimuli [171,177,179]. The suppressive effect of NPCs on T cells was accompanied by a significant suppression of proinflammatory cytokines, such as interleukin (IL)-2, tumor necrosis factor-α, and interferon-γ [177].…”

Section: Immune Modulationmentioning

confidence: 99%

“…This notion emerged from co-culture experiments that showed a striking inhibition of the activation and proliferation of EAE-derived, as well as naive, T cells by NPCs, following stimulation by various stimuli [171,177,179]. The suppressive effect of NPCs on T cells was accompanied by a significant suppression of proinflammatory cytokines, such as interleukin (IL)-2, tumor necrosis factor-α, and interferon-γ [177]. Moreover, NPCs inhibited multiple inflammatory signals, as exemplified by attenuation of the T-cell receptor IL-2-and IL-6-mediated immune cell activation and/or proliferation [179].…”

Section: Immune Modulationmentioning

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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