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1.
Neurol Sci ; 45(3): 849-859, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38169013

RESUMEN

INTRODUCTION: Guillain-Barré syndrome associated with Coronavirus-2-related severe acute respiratory syndrome (COV-GBS) occurs as para- or post-infectious forms, depending on the timing of disease onset. In these two forms, we aimed to compare the cerebrospinal fluid (CSF) and serum proinflammatory cytokine profiles to evaluate differences that could possibly have co-pathogenic relevance. MATERIALS AND METHODS: We studied a retrospective cohort of 26 patients with either post-COV-GBS (n = 15), with disease onset occurring > 7 days after SARS-CoV-2 infection, or para-COV-GBS (n = 11), with disease onset 7 days or less. TNF-α, IL-6, and IL-8 were measured in the serum with SimplePlex™ Ella™ immunoassay. In addition to the para-/post-COV-GBS patients, serum levels of these cytokines were determined in those with non-COVID-associated-GBS (NC-GBS; n = 43), paucisymptomatic SARS-CoV-2 infection without GBS (COVID, n = 20), and in healthy volunteers (HV; n = 12). CSF cytokine levels were measured in patients with para-/post-COV-GBS, in those with NC-GBS (n = 29), or with Alzheimer's disease (AD; n = 24). RESULTS: Serum/CSF cytokine levels did not differ in para- vs post-COV-GBS. We found that SARS-CoV-2 infection raises the serum levels of TNF-α, IL-6, and IL-8, as well as an increase of IL-6 (in serum and CSF) and IL-8 (in CSF) in either NC-GBS or COV-GBS than controls. CSF and serum cytokine levels resulted independent one with another. CONCLUSIONS: The change of cytokines linked to SARS-CoV-2 in COV-GBS appears to be driven by viral infection, although it has unique characteristics in GBS as such and does not account for cases with para- or post-infectious onset.


Asunto(s)
COVID-19 , Síndrome de Guillain-Barré , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Síndrome de Guillain-Barré/complicaciones , Citocinas , Interleucina-6/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa , Estudios Retrospectivos , Interleucina-8
2.
Neurol Sci ; 38(Suppl 2): 217-224, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29030765

RESUMEN

This document presents the guidelines for the cerebrospinal fluid (CSF) analysis and the determination of oligoclonal bands (OCBs) as pivotal tests in neuroinflammatory pathologies of the central nervous system. The guidelines have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on the pathologies in which the CSF analysis is indicated, and, particularly, on those characterized by the presence of OCBs in the intrathecal compartment, indications and limits of CSF analysis and OCB determination, instructions for result interpretation, and agreed laboratory protocols (Appendix) are reported for the communicative community of neurologists and clinical pathologists.


Asunto(s)
Enfermedades Autoinmunes Desmielinizantes SNC/líquido cefalorraquídeo , Enfermedades Autoinmunes Desmielinizantes SNC/inmunología , Bandas Oligoclonales/líquido cefalorraquídeo , Humanos , Bandas Oligoclonales/análisis
3.
Immunology ; 141(3): 328-39, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24116890

RESUMEN

Microglia cells, the resident innate immune cells in the brain, are highly active, extending and retracting highly motile processes through which they continuously survey their microenvironment for 'danger signals' and interact dynamically with surrounding cells. Upon sensing changes in their central nervous system microenvironment, microglia become activated, undergoing morphological and functional changes. Microglia activation is not an 'all-or-none' process, but rather a continuum depending on encountered stimuli, which is expressed through a spectrum of molecular and functional phenotypes ranging from so-called 'classically activated', with a highly pro-inflammatory profile, to 'alternatively activated' associated with a beneficial, less inflammatory, neuroprotective profile. Microglia activation has been demonstrated in most neurological diseases of diverse aetiology and has been implicated as a contributor to neurodegeneration. The possibility to promote microglia's neuroprotective phenotype has therefore become a therapeutic goal. We have focused our discussion on the role of microglia in multiple sclerosis, a prototype of inflammatory, demyelinating, neurodegenerative disease, and on the effect of currently approved or on-trial anti-inflammatory therapeutic strategies that might mediate neuroprotection at least in part through their effect on microglia by modifying their behaviour via a switch of their functional phenotype from a detrimental to a protective one. In addition to pharmaceutical approaches, such as treatment with glatiramer acetate, interferon-ß, fingolimod or dimethyl fumarate, we address the alternative therapeutic approach of treatment with mesenchymal stem cells and their potential role in neuroprotection through their 'calming' effect on microglia.


Asunto(s)
Encéfalo/inmunología , Microglía/inmunología , Esclerosis Múltiple/inmunología , Neuronas/inmunología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Comunicación Celular , Humanos , Trasplante de Células Madre Mesenquimatosas , Microglía/metabolismo , Microglía/patología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas/metabolismo , Neuronas/patología , Fenotipo , Transducción de Señal
4.
Stem Cells ; 30(9): 2044-53, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22821677

RESUMEN

Mesenchymal stem cells (MSC) display a remarkable ability to modulate the immune response and protect the central nervous system mainly through the release of soluble factors in a paracrine fashion, affecting the functional behavior of cells in the tissues. Here we investigated the effect of the interaction between MSC and microglia in vitro, and we dissected the molecular and cellular mechanisms of this crosstalk. We demonstrated that MSC impair microglia activation by inflammatory cues through the inhibition of the expression and release of inflammatory molecules and stress-associated proteins. We showed that MSC significantly increase microglial expression and release of molecules associated with a neuroprotective phenotype such as CX3CR1, nuclear receptor 4 family, CD200 receptor, and insulin growth factor 1. Interestingly, MSC can enhance functional changes on microglia as depicted by the increase of intracellular calcium concentration and phagocytic activity. This last event is associated with an increased expression of triggering receptor expressed on myeloid cells-2, an innate immune receptor involved in phagocytosis in the absence of inflammation. The observed effects on CX3CR1-expressing microglia are due to the release of CX3CL1 by MSC, driven by inflammatory signals, as demonstrated by the reversal of the observed results when CX3CL1 expression was silenced in MSC or its release was blocked. Finally, we showed that exogenous CX3CL1 induce phenotypic and functional changes of microglia similar to those induced by MSC. These findings demonstrate that MSC instruct, through the release of CX3CL1, microglia responsiveness to proinflammatory signals by modulating constitutive "calming" receptors, typically expressed by "steady-state microglia" thus switching microglia from a detrimental phenotype to a neuroprotective one.


Asunto(s)
Comunicación Celular/fisiología , Quimiocina CX3CL1/metabolismo , Células Madre Mesenquimatosas/metabolismo , Microglía/metabolismo , Animales , Procesos de Crecimiento Celular/fisiología , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos C57BL , Microglía/citología , Fagocitosis
5.
Mol Med ; 18: 794-804, 2012 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-22481270

RESUMEN

Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 106) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [³H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase- and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [³H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Trasplante de Células Madre Mesenquimatosas , Actividad Motora , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/mortalidad , Animales , Ácido Aspártico/metabolismo , Movimiento Celular , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/fisiopatología , Progresión de la Enfermedad , Femenino , Humanos , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Transgénicos , Estrés Oxidativo , Médula Espinal/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1
6.
Cells ; 11(23)2022 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-36497181

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes' neurotoxicity can reduce MN death. Our previous studies showed the beneficial effect of mesenchymal stem cell (MSC) administration in SOD1G93A ALS mice, but the mechanisms are still unclear. We postulated that the effects could be mediated by extracellular vesicles (EVs) secreted by MSCs. We investigated, by immunohistochemical, molecular, and in vitro functional analyses, the activity of MSC-derived EVs on the pathological phenotype and neurotoxicity of astrocytes isolated from the spinal cord of symptomatic SOD1G93A mice and human astrocytes (iAstrocytes) differentiated from inducible neural progenitor cells (iNPCs) of ALS patients. In vitro EV exposure rescued mouse and human ALS astrocytes' neurotoxicity towards MNs. EVs significantly dampened the pathological phenotype and neuroinflammation in SOD1G93A astrocytes. In iAstrocytes, exposure to EVs increased the antioxidant factor Nrf2 and reduced reactive oxygen species. We previously found nine miRNAs upregulated in MSC-derived EVs. Here, the transfection of SOD1G93A astrocytes with single miRNA mimics reduced astrocytes' activation and the expression of neuroinflammatory factors. Moreover, miR-466q and miR-467f mimics downregulate Mapk11, while miR-466m-5p and miR-466i-3p mimics promote the nuclear translocation of Nrf2. In iAstrocytes, transfection with miR-29b-3p mimic upregulated NQO1 antioxidant activity and reduced neurotoxicity towards MNs. MSC-derived EVs modulate astrocytes' reactive phenotype and neurotoxicity through anti-inflammatory and antioxidant-shuttled miRNAs, thus representing a therapeutic strategy in ALS.


Asunto(s)
Esclerosis Amiotrófica Lateral , Vesículas Extracelulares , Células Madre Mesenquimatosas , MicroARNs , Enfermedades Neurodegenerativas , Humanos , Ratones , Animales , Esclerosis Amiotrófica Lateral/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Ratones Transgénicos , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo
7.
Sci Rep ; 11(1): 1740, 2021 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-33462263

RESUMEN

Mesenchymal stromal/stem cells (MSCs) are characterized by neuroprotective, immunomodulatory, and neuroregenerative properties, which support their therapeutic potential for inflammatory/neurodegenerative diseases, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). One mode of action through which MSCs exert their immunomodulatory effects is release of extracellular vesicles that carry proteins, mRNAs, and microRNAs (miRNAs), which, once transferred, modify the function of target cells. We identified nine miRNAs significantly dysregulated in IFN-γ-primed MSCs, but present at different levels in their derived small extracellular vesicles (s-EV). We show that miR-467f and miR-466q modulate the pro-inflammatory phenotype of activated N9 microglia cells and of primary microglia acutely isolated from late symptomatic SOD1G93A mice, a murine ALS model, by downregulating Tnf and Il1b expression. Further analysis of the mode of action of miR-467f and miR-466q indicated that they dampen the pro-inflammatory phenotype of microglia by modulating p38 MAPK signaling pathway via inhibition of expression of their target genes, Map3k8 and Mk2. Finally, we demonstrated that in vivo administration of s-EV leads to decreased expression of neuroinflammation markers in the spinal cord of EAE-affected mice, albeit without affecting disease course. Overall, our data suggest that MSC-derived exosomes could affect neuroinflammation possibly through specific immunomodulatory miRNAs acting on microglia.


Asunto(s)
Esclerosis Amiotrófica Lateral/terapia , Encefalitis/terapia , Vesículas Extracelulares/genética , Inflamación/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , MicroARNs/administración & dosificación , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Encefalitis/genética , Encefalitis/metabolismo , Encefalitis/patología , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , Microglía/metabolismo , Neuroprotección , Transducción de Señal
8.
Neural Plast ; 2010: 534925, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-21331297

RESUMEN

Although many studies have shown that administration of stem cells after focal cerebral ischemia improves brain damage, very little data are available concerning the damage induced by global cerebral ischemia. The latter causes neuronal death in selectively vulnerable areas, including the hippocampal CA1 region. We tested the hypothesis that intravenous infusion of bone marrowderived stromal cells (mesenchimal stem cells, MSC) reduce brain damage after transient global ischemia. In adult male Sprague-Dawley rats transient global ischemia was induced using bilateral common carotid artery occlusion for 20 min in addition to controlled hypotension. Five days after, the animals were anaesthetized with urethane and the brain was fixed, sectioned and stained with hematoxylin-eosin to investigate histological damage. MSC did not fully protect against ischemic damage, as the number of viable neurons in this group was lower than in normal (sham-operated) rats. However, in MSC-treated rats the number of viable CA1 pyramidal neurons was significally higher than in rats that had been subjected to ischemia but not treated with MSC. We conclude that intravenous administration of MSC after transient global ischemia reduces hippocampal damage.


Asunto(s)
Isquemia Encefálica/patología , Isquemia Encefálica/terapia , Diferenciación Celular/fisiología , Trasplante de Células Madre Mesenquimatosas/métodos , Neuronas/fisiología , Animales , Supervivencia Celular/fisiología , Células Cultivadas , Modelos Animales de Enfermedad , Supervivencia de Injerto/fisiología , Hipocampo/citología , Hipocampo/fisiología , Humanos , Infusiones Intravenosas , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Ratas , Ratas Sprague-Dawley
9.
Pharmacol Ther ; 111(3): 555-66, 2006 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-16442633

RESUMEN

In this review we will discuss the unique features that make the central nervous system (CNS) a specialized microenvironment where immune responses are tightly regulated in order to properly face pathogens without damaging the neural cells. We will show how every paradigm of this theoretical model has been addressed by the scientific literature over the past decades providing new insights on the immune response within the CNS. In particular, new light has been shed on the trafficking of the immune cells inside and outside the CNS. Dendritic cells (DCs) have been described in the context of structures in direct contact with the cerebrospinal fluid (CSF) and their migration, upon antigen encounter, outside the CNS into deep cervical lymph nodes (DCLNs) has been further clarified. T-cells, B-cells, and antibody-secreting cells (ASCs) have been found in the CSF and CNS parenchymal lesions of inflammatory disorders and their phenotype depicted. Moreover, in chronically inflamed CNS, ectopic lymphoid structures have been observed and a germinal center reaction similar to the one found in peripheral lymph nodes has been described. These structures may play a role in the maintenance and expansion of the local autoimmune response. Although the complex interactions between immune and neural cells still remain far to be elucidated, the data discussed here suggest that the physiopathology of the adaptive immune response inside the CNS mimics, although in a mitigated fashion, what occurs in other organs and tissues.


Asunto(s)
Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inflamación/inmunología , Esclerosis Múltiple/inmunología , Animales , Linfocitos B/inmunología , Barrera Hematoencefálica , Movimiento Celular , Humanos , Linfocitos T/inmunología
10.
J Neurol ; 264(5): 973-978, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28382419

RESUMEN

The analysis of paired cerebrospinal fluid (CSF) and serum samples with isolectric focusing (IEF) can yield different patterns which can be of aid in the differential diagnosis of central nervous system (CNS) disorders. Rarely, a single CSF-restricted IgG band, which is not included within these patterns, can be detected in association with inflammatory disorders, multiple sclerosis (MS) above all. However, the diagnostic meaning of this abnormality is still uncertain. The main aim of our multicenter study was to establish the frequency and disease associations of single CSF IgG bands. Differences in the CSF profiles between MS and other diseases, and the follow-up patterns were also evaluated. Medical records of patients who underwent CSF analysis, which included IEF, over a 11.5-year period were retrospectively scrutinized at the participating centers, which used similar IEF techniques. One hundred and fifty-one of 9422 CSF reports (1.6%) showed single CSF-restricted IgG bands. Of the 129 patients with a definite diagnosis, 58.2% had CNS inflammatory-demyelinating diseases (the most frequent being MS: 21.7%), 6.2% tumours, 5.4% inflammatory peripheral nervous system diseases and 30.2% miscellaneous diseases. At follow-up, 3 out of the 10 patients with a repeated CSF analysis had developed an oligoclonal band pattern. Our findings indicate that single CSF IgG bands tend to associate with diseases characterized by the involvement of intrathecal humoral immune responses, and strongly support the notion that this abnormality should be regularly reported, thus alerting clinicians of possible inflammatory disorders of the CNS.


Asunto(s)
Enfermedades del Sistema Nervioso Central/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso Central/diagnóstico , Inmunoglobulina G/líquido cefalorraquídeo , Bandas Oligoclonales/líquido cefalorraquídeo , Adulto , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Focalización Isoeléctrica , Italia , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
11.
J Leukoc Biol ; 73(5): 584-90, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12714572

RESUMEN

The recruitment of lymphocytes across the blood brain barrier (BBB) is mediated by adhesion molecules and chemokines. The expression of activation markers and of chemokine receptors on T cells homing to the nervous system (NS) may help define their functional state. In the cerebrospinal fluid (CSF) of subjects with inflammatory neurological diseases (IND), including multiple sclerosis, we observed an increased number of T cells coexpressing CXCR3 and CCR5 as well as T cells with a CD45RO+ CCR7+ CD27+ memory phenotype. A subset of CCR7+ T cells coexpressed CXCR3 and CCR5. We also detected an increased number of interferon-gamma-producing T cells in the CSF compared with peripheral blood, mostly but not exclusively in the CD45RO+ CCR7- CD27- compartment. T helper 1 (Th1) clones, established from the CSF of individuals with IND and from a healthy subject, similarly migrated to CXCL10, CXCL12, and CCL5. CXCL10, CXCL12, and CCL19 were increased in the CSF of individuals with neuroinflammation. These findings suggest that CSF is enriched in Th1-polarized memory T cells capable of differentiating into effector cells upon antigen encounter. These cells are recruited into the CSF by inducible chemokines. Thus, CSF represents a transitional station for T cells trafficking to and from the NS.


Asunto(s)
Esclerosis Múltiple/líquido cefalorraquídeo , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Diferenciación Celular , Movimiento Celular , Quimiocina CCL19 , Quimiocina CXCL10 , Quimiocina CXCL12 , Quimiocinas CC/biosíntesis , Quimiocinas CC/genética , Quimiocinas CXC/biosíntesis , Quimiocinas CXC/genética , Quimiocinas CXC/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Encefalitis/líquido cefalorraquídeo , Encefalitis/inmunología , Femenino , Humanos , Memoria Inmunológica/inmunología , Inmunofenotipificación , Interferón gamma/metabolismo , Antígenos Comunes de Leucocito/análisis , Neuroborreliosis de Lyme/líquido cefalorraquídeo , Neuroborreliosis de Lyme/inmunología , Activación de Linfocitos , Masculino , Meningitis/líquido cefalorraquídeo , Meningitis/inmunología , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/líquido cefalorraquídeo , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Receptores CCR5/análisis , Receptores CCR7 , Receptores CXCR3 , Receptores de Quimiocina/análisis , Células TH1/inmunología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisis
12.
J Neuroimmunol ; 148(1-2): 146-53, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-14975595

RESUMEN

Alpha-lipoic acid (alpha-LA) is a neuroprotective metabolic antioxidant that has been shown to cross the blood brain barrier. We tested whether alpha-LA is capable to prevent MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). Daily oral administration of alpha-LA, starting at the time of immunization, significantly prevented EAE progression as compared to control mice. This was associated with a reduction of CNS infiltrating T cells and macrophages as well as decreased demyelination. We then tested alpha-LA in a therapeutic protocol aimed at suppressing EAE after its onset. Intraperitoneal (i.p.), but not oral, administration of alpha-LA significantly prevented disease progression when compared to vehicle-treated controls. Similarly, we observed significant reduction of demyelination and inflammatory infiltration. This clinical effect was not due to an impairment of MOG35-55 recognition by encephalitogenic T cells. In contrast, MOG-specific T cells showed a decreased production of IFNgamma and IL-4, suggesting an immunosuppressive activity on both Th1 and Th2 cytokines. In addition, alpha-LA inhibited the proteolytic activity of MMP2 and MMP9 only at very high doses. Our data indicate that alpha-LA can effectively interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports further studies on the use of alpha-LA as a potential therapy for MS.


Asunto(s)
Antioxidantes/uso terapéutico , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/prevención & control , Ácido Tióctico/uso terapéutico , Análisis de Varianza , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Encefalomielitis Autoinmune Experimental/inducido químicamente , Femenino , Fibrosarcoma/tratamiento farmacológico , Glicoproteínas , Inmunización , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Linfocitos T/efectos de los fármacos
13.
Best Pract Res Clin Haematol ; 24(1): 59-64, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21396593

RESUMEN

Bone marrow (BM) derived mesenchymal stem cells (MSC) differentiate into cells of the mesodermal lineage but also, under certain experimental circumstances, into cells of the neuronal and glial lineage. Their therapeutic translation has been significantly boosted by the demonstration that MSC display significant also anti-proliferative, anti-inflammatory and anti-apoptotic features. These properties have been exploited in the effective treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis where the inhibition of the autoimmune response resulted in a significant neuroprotection. A significant rescue of neural cells has been achieved also when MSC were administered in experimental brain ischemia and in animals undergoing brain or spinal cord injury. In these experimental conditions BM-MSC therapeutic effects are likely to depend on paracrine mechanisms mediated by the release of growth factors, anti-apoptotic molecules and anti-inflammatory cytokines creating a favorable environment for the regeneration of neurons, remyelination and improvement of cerebral flow. For potential clinical application BM-MSC offer significant practical advantages over other types of stem cells since they can be obtained from the adult BM and can be easily cultured and expanded in vitro under GMP conditions displaying a very low risk of malignant transformation. This review discusses the targets and mechanisms of BM-MSC mediated neuroprotection.


Asunto(s)
Células Madre Mesenquimatosas/fisiología , Regeneración Nerviosa/fisiología , Neuronas/fisiología , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Transdiferenciación Celular/fisiología , Encefalomielitis Autoinmune Experimental/prevención & control , Trasplante de Células Madre Mesenquimatosas , Ratones , Esclerosis Múltiple/terapia , Traumatismos de la Médula Espinal/terapia
14.
Blood ; 107(1): 367-72, 2006 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-16141348

RESUMEN

Human mesenchymal stem cells (hMSCs) suppress T-cell and dendritic-cell function and represent a promising strategy for cell therapy of autoimmune diseases. Nevertheless, no information is currently available on the effects of hMSCs on B cells, which may have a large impact on the clinical use of these cells. hMSCs isolated from the bone marrow and B cells purified from the peripheral blood of healthy donors were cocultured with different B-cell tropic stimuli. B-cell proliferation was inhibited by hMSCs through an arrest in the G0/G1 phase of the cell cycle and not through the induction of apoptosis. A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments. hMSCs inhibited B-cell differentiation because IgM, IgG, and IgA production was significantly impaired. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B cells. B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs. These results further support the potential therapeutic use of hMSCs in immune-mediated disorders, including those in which B cells play a major role.


Asunto(s)
Linfocitos B/fisiología , Comunicación Celular/fisiología , Células Madre Mesenquimatosas/fisiología , Linfocitos B/citología , Factores Biológicos/metabolismo , Factores Biológicos/fisiología , Diferenciación Celular , Proliferación Celular , Quimiocinas/genética , Quimiotaxis , Técnicas de Cocultivo , Regulación de la Expresión Génica , Humanos , Células Madre Mesenquimatosas/metabolismo , Fase de Descanso del Ciclo Celular
15.
Blood ; 106(5): 1755-61, 2005 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-15905186

RESUMEN

We studied the immunoregulatory features of murine mesenchymal stem cells (MSCs) in vitro and in vivo. MSCs inhibited T-cell receptor (TCR)-dependent and -independent proliferation but did not induce apoptosis on T cells. Such inhibition was paired with a decreased interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and was partially reversed by interleukin-2 (IL-2). Thus, we used MSCs to treat myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. We injected intravenously 1 x 10(6) MSCs before disease onset (preventive protocol) and at different time points after disease occurrence (therapeutic protocol). MSC administration before disease onset strikingly ameliorated EAE. The therapeutic scheme was effective when MSCs were administered at disease onset and at the peak of disease but not after disease stabilization. Central nervous system (CNS) pathology showed decreased inflammatory infiltrates and demyelination in mice that received transplants of MSCs. T-cell response to MOG and mitogens from MSC-treated mice was inhibited and restored by IL-2 administration. Upon MSC transfection with the enhanced green fluorescent protein (eGFP), eGFP(+) cells were detected in the lymphoid organs of treated mice. These data suggest that the immunoregulatory properties of MSCs effectively interfere with the autoimmune attack in the course of EAE inducing an in vivo state of T-cell unresponsiveness occurring within secondary lymphoid organs.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/prevención & control , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/inmunología , Linfocitos T/inmunología , Animales , Proliferación Celular , Células Cultivadas , Anergia Clonal/inmunología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Glicoproteínas , Proteínas Fluorescentes Verdes/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-2/farmacología , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Péptidos , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Linfocitos T/efectos de los fármacos , Factor de Necrosis Tumoral alfa/inmunología
16.
Proc Natl Acad Sci U S A ; 101(30): 11064-9, 2004 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-15263096

RESUMEN

Clonally expanded populations of B cells carrying somatic mutations of Ig variable (V) region genes have been detected in the CNS of subjects with multiple sclerosis (MS), suggesting that a process of B cell affinity maturation with ensuing production of potentially pathogenic autoantibodies may occur inside the CNS. Here, we have characterized the B cell subsets present in the cerebrospinal fluid (CSF) of MS patients and of individuals with other inflammatory neurological disorders by flow cytometry. CD19(+)CD38(high+)CD77(+), Ki67(+), Bcl-2(-) centroblasts, i.e., a B cell subset found exclusively in secondary lymphoid organs, were detected in the CSF but not in paired peripheral blood from both patient groups. CD27(+)IgD(-) memory B cells, i.e., cells with hyper-mutated IgV genes, were significantly increased in the CSF vs. paired peripheral blood and displayed up-regulation of the CD80 and CD86 costimulatory molecules and of CC chemokine receptor (CCR) 1, CCR2, and CCR4 in both patient groups. Lymphotoxin-alpha, CXC ligand (CXCL) 12, and CXCL13, key mediators of lymphoid neogenesis, were present in the CSF from patients with MS and other inflammatory neurological disorders and were expressed in MS brain tissue, with selective localization in the outer layer of the capillary vessel wall. In conclusion, this study suggests that a compartmentalized B cell response occurs within the CNS during an ongoing inflammatory reaction, through a recapitulation of all stages of B cell differentiation observed in secondary lymphoid organs. The presence of lymphotoxin-alpha, CXCL12, and CXCL13 in the CNS may provide favorable microenvironmental conditions for these events.


Asunto(s)
Linfocitos B/inmunología , Sistema Nervioso Central/inmunología , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/inmunología , Antígenos CD/análisis , Antígenos CD/líquido cefalorraquídeo , Antígenos CD/inmunología , Antígenos CD19/análisis , Antígenos CD19/líquido cefalorraquídeo , Antígenos CD19/inmunología , Subgrupos de Linfocitos B/inmunología , Linfocitos B/patología , Diferenciación Celular , Citometría de Flujo , Humanos , Inmunoglobulina D/análisis , Esclerosis Múltiple/patología
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