Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy

Mansilla, María José; Presas-Rodríguez, Silvia; Teniente-Serra, Aina; González-Larreategui, Íñigo; Quirant‐Sánchez, Bibiana; Fondelli, Federico; Djedović, Neda; Iwaszkiewicz-Grześ, Dorota; Chwojnicki, Kamil; Miljković, Djordje; Trzonkowski, Piotr; Ramo-Tello, Cristina; Martínez-Cáceres, Eva

doi:10.1038/s41423-020-00618-z

Cited by 35 publications

(23 citation statements)

References 180 publications

(267 reference statements)

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“…A major disadvantage of this form of therapy is the necessity to use tolerogenic DCs loaded with multiple myelin antigens as the immune response among the patients is heterogeneous, and the antigen spreading must always be considered. Although experimental tolDC therapy was effective in early stages of EAE, there was no beneficial effect of its use for chronic EAE [129,[133][134][135][136]. Similar results should be expected in accordance with MS in humans.…”

Section: Dendritic Cells In Ms Therapymentioning

confidence: 55%

“…Similar results should be expected in accordance with MS in humans. In the early stage of inflammation, when the autoimmune reaction targets major myelin antigens, the tolDC-based therapy should be the most effective [136].…”

Section: Dendritic Cells In Ms Therapymentioning

confidence: 99%

“…Actually, two independent phase I clinical trials utilizing tolDC are taking place, and one has already finished [136,137]. A phase Ib clinical trial with dexamethasoneinduced tolerogenic DC loaded with myelin antigens or Aquaporin 4 that finished in 2019 confirmed safety of the therapy and provided the proof of concept for use of tolerance inducing DCs in future.…”

Section: Tolerogenic Dcs In Clinical Trialsmentioning

confidence: 99%

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Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment

2021

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Multiple sclerosis (MS) is common neurological disease of the central nervous system (CNS) affecting mostly young adults. Despite decades of studies, its etiology and pathogenesis are not fully unraveled and treatment is still insufficient. The vast majority of studies suggest that the immune system plays a major role in MS development. This is also supported by the effectiveness of currently available MS treatments that target immunocompetent cells. In this review, the role of antigen-presenting cells (APC) in MS development as well as the novel therapeutic options targeting those cells in MS are presented. It is known that in MS, peripheral self-antigen-specific immune cells are activated during antigen presentation process and they enter the CNS through the disrupted blood–brain barrier (BBB). Myelin-reactive CD4+ T-cells can be activated by dendritic cells, infiltrating macrophages, microglia cells, or B-cells, which all express MHC class II molecules. There are also suggestions that brain endothelial cells may act as non-professional APCs and present myelin-specific antigens with MHC class II. Similarly, astrocytes, the major glial cells in the CNS, were shown to act as non-professional APCs presenting myelin antigens to autoreactive T-cells. Several currently available MS drugs such as natalizumab, fingolimod, alemtuzumab, and ocrelizumab may modulate antigen presentation in MS. Another way to use this mechanism in MS treatment may be the usage of specific tolerogenic dendritic cells or the induction of tolerance to myelin antigens by peptide vaccines.

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Section: Dendritic Cells In Ms Therapymentioning

confidence: 55%

Section: Dendritic Cells In Ms Therapymentioning

confidence: 99%

Section: Tolerogenic Dcs In Clinical Trialsmentioning

confidence: 99%

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Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment

2021

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“…These data may suggest that targeting SELENOI in T cells may represent a potential therapeutic approach to treating MS. Indeed, cell-based therapies have been proposed for restoring homeostasis in MS patients such as tolerogenic dendritic cells, Tregs, mesenchymal stem cells, and vaccination with T cells [ 64 ]. Interfering with SELENOI activity to skew Th17/Treg cells toward a tolerogenic phenotype certainly presents its challenges, but may provide a new cell-based therapeutic approach for this or other autoimmune disorders.…”

Section: Selenoi and T Helper Cell Differentiationmentioning

confidence: 99%

Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation

Martinez-Rodriguez

Hoffmann

2021

IJMS

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The selenoprotein family includes 25 members, many of which are antioxidant or redox regulating enzymes. A unique member of this family is Selenoprotein I (SELENOI), which does not catalyze redox reactions, but instead is an ethanolamine phosphotransferase (Ept). In fact, the characteristic selenocysteine residue that defines selenoproteins lies far outside of the catalytic domain of SELENOI. Furthermore, data using recombinant SELENOI lacking the selenocysteine residue have suggested that the selenocysteine amino acid is not directly involved in the Ept reaction. SELENOI is involved in two different pathways for the synthesis of phosphatidylethanolamine (PE) and plasmenyl PE, which are constituents of cellular membranes. Ethanolamine phospholipid synthesis has emerged as an important process for metabolic reprogramming that occurs in pluripotent stem cells and proliferating tumor cells, and this review discusses roles for upregulation of SELENOI during T cell activation, proliferation, and differentiation. SELENOI deficiency lowers but does not completely diminish de novo synthesis of PE and plasmenyl PE during T cell activation. Interestingly, metabolic reprogramming in activated SELENOI deficient T cells is impaired and this reduces proliferative capacity while favoring tolerogenic to pathogenic phenotypes that arise from differentiation. The implications of these findings are discussed related to vaccine responses, autoimmunity, and cell-based therapeutic approaches.

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“…Multiple sclerosis (MS), an autoimmune, chronic inflammatory demyelinating disease of the central nervous system, is the number one cause of neurological disability among adults, affecting women twice to three times as often as men (1)(2)(3). It is one of the main disability diseases in the global population (4). The clinical features of MS are dissemination in space and time (5).…”

Section: Introductionmentioning

confidence: 99%

Identification and Clinical Validation of Key Extracellular Proteins as the Potential Biomarkers in Relapsing-Remitting Multiple Sclerosis

Chen

Yin

et al. 2021

Front. Immunol.

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BackgroundMultiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mediated by autoimmunity. No objective clinical indicators are available for the diagnosis and prognosis of MS. Extracellular proteins are most glycosylated and likely to enter into the body fluid to serve as potential biomarkers. Our work will contribute to the in-depth study of the functions of extracellular proteins and the discovery of disease biomarkers.MethodsMS expression profiling data of the human brain was downloaded from the Gene Expression Omnibus (GEO). Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases. GO and KEGG were used to analyze the function and pathway of EP-DEGs. STRING, Cytoscape, MCODE and Cytohubba were used to construct a protein-protein interaction (PPI) network and screen key EP-DEGs. Key EP-DEGs levels were detected in the CSF of MS patients. ROC curve and survival analysis were used to evaluate the diagnostic and prognostic ability of key EP-DEGs.ResultsWe screened 133 EP-DEGs from DEGs. EP-DEGs were enriched in the collagen-containing extracellular matrix, signaling receptor activator activity, immune-related pathways, and PI3K-Akt signaling pathway. The PPI network of EP-DEGs had 85 nodes and 185 edges. We identified 4 key extracellular proteins IL17A, IL2, CD44, IGF1, and 16 extracellular proteins that interacted with IL17A. We clinically verified that IL17A levels decreased, but Del-1 and resolvinD1 levels increased. The diagnostic accuracy of Del-1 (AUC: 0.947) was superior to that of IgG (AUC: 0.740) with a sensitivity of 82.4% and a specificity of 100%. High Del-1 levels were significantly associated with better relapse-free and progression-free survival.ConclusionIL17A, IL2, CD44, and IGF1 may be key extracellular proteins in the pathogenesis of MS. IL17A, Del-1, and resolvinD1 may co-regulate the development of MS and Del-1 is a potential biomarker of MS. We used bioinformatics methods to explore the biomarkers of MS and validated the results in clinical samples. The study provides a theoretical and experimental basis for revealing the pathogenesis of MS and improving the diagnosis and prognosis of MS.

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Paving the way towards an effective treatment for multiple sclerosis: advances in cell therapy

Cited by 35 publications

References 180 publications

Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment

Targeting Antigen-Presenting Cells in Multiple Sclerosis Treatment

Roles for Selenoprotein I and Ethanolamine Phospholipid Synthesis in T Cell Activation

Identification and Clinical Validation of Key Extracellular Proteins as the Potential Biomarkers in Relapsing-Remitting Multiple Sclerosis

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