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1.
Brain Behav Immun ; 62: 332-343, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28238951

RESUMO

Therapies with both immunomodulatory and neuroprotective properties are thought to have the greatest promise in reducing the severity and progression of multiple sclerosis (MS). Several reactive oxygen (ROS) and reactive nitrogen species (RNS) are implicated in inflammatory-mediated damage to the central nervous system (CNS) in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a stable nitroxide radical with potent antioxidant activity. The goal of our studies was to investigate the immunomodulatory effects and therapeutic potential of orally-delivered TEMPOL in the mouse EAE model. Mice receiving TEMPOL chow ad libitum for 2weeks prior to induction of active EAE showed delayed onset and reduced incidence of disease compared to control-fed animals. Reduced disease severity was associated with limited microglial activation and fewer inflammatory infiltrates. TEMPOL's effects were immunomodulatory, not immunosuppressive: T cells produced less interferon-γ and tumor necrosis factor-α, and TEMPOL-fed mice exhibited a shift towards TH2-type antibody responses. Both myeloid and myeloid-dendritic cells of TEMPOL-fed EAE animals had significantly lower levels of MHC class II expression than controls; CD40 was also significantly reduced. TEMPOL administration was associated with an enrichment of CD8+ T cell populations and CD4+FoxP3+ regulatory populations. TEMPOL reduced the severity of clinical disease when administered after the induction of disease, and also after the onset of clinical symptoms. To exclude effects on T cell priming in vivo, TEMPOL was tested with the passive transfer of encephalitogenic T cells and was found to reduce the incidence and peak severity of disease. Protection was associated with reduced infiltrates and a relative sparing of neurofilaments and axons. The ability of oral TEMPOL to reduce inflammation and axonal damage and loss demonstrate both anti-inflammatory and protective properties, with significant promise for the treatment of MS and related neurological disorders.


Assuntos
Óxidos N-Cíclicos/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fatores Imunológicos/farmacologia , Microglia/efeitos dos fármacos , Esclerose Múltipla/diagnóstico por imagem , Administração Oral , Animais , Óxidos N-Cíclicos/uso terapêutico , Encefalomielite Autoimune Experimental/imunologia , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Camundongos , Esclerose Múltipla/imunologia , Marcadores de Spin , Resultado do Tratamento
2.
J Immunol ; 189(6): 2897-908, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22888134

RESUMO

Genetic susceptibility to multiple sclerosis (MS) has been linked to the HLA-DR15 haplotype consisting of DRB1*15:01(DR2b) and DRB5*01:01(DR2a) alleles. Given almost complete linkage disequilibrium of the two alleles, recent studies suggested differential roles in susceptibility (DR2b) or protection from MS (DR2a). Our objective was to assess the potential contribution of DR2a to disease etiology in MS using a humanized model of autoimmunity. To assess the potential contribution of DR2a to disease etiology, we created DR2a humanized transgenic (Tg) mice and subsequently crossed them to Tg mice expressing TL3A6, an MS patient-derived myelin basic protein 83-99-specific TCR. In TL3A6/DR2a Tg mice, CD4 Tg T cells escape thymic and peripheral deletion and initiate spontaneous experimental autoimmune encephalomyelitis (EAE) at low rates, depending on the level of DR2a expression. The ability to induce active EAE was also increased in animals expressing higher levels of DR2a. Inflammatory infiltrates and neuronal damage were present throughout the spinal cord, consistent with a classical ascending EAE phenotype with minor involvement of the cerebellum, brainstem, and peripheral nerve roots in spontaneous, as well as actively induced, disease. These studies emphasize the pathologic contribution of the DR2a allele to the development of autoimmunity when expressed as the sole MHC class II molecule, as well as strongly argue for DR2a as a contributor to the CNS autoimmunity in MS.


Assuntos
Predisposição Genética para Doença/genética , Cadeias HLA-DRB5/genética , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Transferência Adotiva/métodos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Cadeias HLA-DRB5/biossíntese , Cadeias HLA-DRB5/fisiologia , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Esclerose Múltipla/etiologia , Receptores de Antígenos de Linfócitos T/biossíntese , Receptores de Antígenos de Linfócitos T/imunologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/patologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/patologia
3.
Brain ; 136(Pt 4): 1035-47, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23518706

RESUMO

The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.


Assuntos
Sistema Nervoso Central/fisiopatologia , Doenças Desmielinizantes/fisiopatologia , Endotelina-2/fisiologia , Mediadores da Inflamação/fisiologia , Regeneração Nervosa/fisiologia , Receptor de Endotelina B/fisiologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Doenças Desmielinizantes/metabolismo , Endotelina-2/biossíntese , Endotelina-2/metabolismo , Feminino , Cabras , Humanos , Mediadores da Inflamação/metabolismo , Camundongos , Análise em Microsséries/instrumentação , Análise em Microsséries/métodos , Coelhos , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Receptor de Endotelina B/agonistas
4.
Mult Scler J Exp Transl Clin ; 9(2): 20552173231169463, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37139460

RESUMO

Background: CombiRx was a randomized, double-blind, placebo-controlled phase 3 trial in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients randomized to intramuscular interferon beta-1a (IM IFN beta-1a), glatiramer acetate (GA), or both therapies. Objective: This analysis investigated changes in serum neurofilament light-chain (sNfL) levels in response to treatment and assessed baseline sNfL as a predictor of relapse. Methods: RRMS patients treated with IM IFN beta-1a 30 µg weekly + placebo (n = 159), GA 20 mg/mL daily + placebo (n = 172), or IM IFN beta-1a + GA (n = 344) were included. A linear mixed model compared sNfL values over time. Cox regression models analyzed baseline sNfL and gadolinium-enhancing (Gd+) lesions as predictors of relapse. Results: In all treatment arms, the proportion of patients with sNfL ≥16 pg/mL decreased significantly from baseline to 6 months and was maintained at 36 months. A significantly higher percentage of patients with both baseline sNfL ≥16 pg/mL and ≥1 Gd+ lesion experienced relapses within 90 days compared to patients with sNfL <16 pg/mL and/or no Gd+ lesions. Conclusion: sNfL levels were reduced within 6 months and remained low at 36 months. Results suggest that the combination of lesion activity and sNfL was a stronger predictor of relapse than either factor alone.

5.
J Exp Med ; 201(5): 805-16, 2005 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-15738052

RESUMO

Clinical trials have indicated that autologous hematopoietic stem cell transplantation (HSCT) can persistently suppress inflammatory disease activity in a subset of patients with severe multiple sclerosis (MS), but the mechanism has remained unclear. To understand whether the beneficial effects on the course of disease are mediated by lympho-depletive effects alone or are sustained by a regeneration of the immune repertoire, we examined the long-term immune reconstitution in patients with MS who received HSCT. After numeric recovery of leukocytes, at 2-yr follow-up there was on average a doubling of the frequency of naive CD4(+) T cells at the expense of memory T cells. Phenotypic and T cell receptor excision circle (TREC) analysis confirmed a recent thymic origin of the expanded naive T cell subset. Analysis of the T cell receptor repertoire showed the reconstitution of an overall broader clonal diversity and an extensive renewal of clonal specificities compared with pretherapy. These data are the first to demonstrate that long-term suppression of inflammatory activity in MS patients who received HSCT does not depend on persisting lymphopenia and is associated with profound qualitative immunological changes that demonstrate a de novo regeneration of the T cell compartment.


Assuntos
Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Transplante de Células-Tronco , Timo/imunologia , Adulto , Sequência de Aminoácidos , Antígenos CD34/metabolismo , Feminino , Seguimentos , Humanos , Memória Imunológica/imunologia , Leucócitos/imunologia , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Esclerose Múltipla/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T/química , Linfócitos T/imunologia , Linfócitos T/patologia , Timo/citologia , Transplante Autólogo , Resultado do Tratamento
6.
J Exp Med ; 200(2): 223-34, 2004 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-15263029

RESUMO

Amino acid residues 111-129 represent an immunodominant epitope of myelin basic protein (MBP) in humans with human leukocyte antigen (HLA)-DRB1*0401 allele(s). The MBP 111-129-specific T cell clone MS2-3C8 was repeatedly isolated from a patient with multiple sclerosis (MS), suggesting an involvement of MS2-3C8 T cells in the pathogenesis. To address the pathogenic potential of the MS2-3C8 T cell clone, we generated transgenic (Tg) mice expressing its T cell receptor and restriction element, HLA-DRB1*0401, to examine the pathogenic characteristics of MS2-3C8 Tg T cells by adoptive transfer into HLA-DRB1*0401 Tg mice. In addition to the ascending paralysis typical of experimental autoimmune encephalomyelitis, mice displayed dysphagia due to restriction in jaw and tongue movements and abnormal gait. In accordance with the clinical phenotype, infiltrates of MS2-3C8 Tg T cells and inflammatory lesions were predominantly located in the brainstem and the cranial nerve roots in addition to the spinal cord and spinal nerve roots. Together, these data suggest a pathogenic role of MBP-specific T cells in inflammatory demyelination within the brainstem and cranial nerve roots during the progression of MS. This notion may help to explain the clinical and pathological heterogeneity of MS.


Assuntos
Antígenos HLA-DR/metabolismo , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Sequência de Aminoácidos , Animais , Separação Celular , Citocinas/biossíntese , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/metabolismo , Citometria de Fluxo , Cadeias HLA-DRB1 , Humanos , Imuno-Histoquímica , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Esclerose Múltipla/metabolismo , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Fatores de Tempo
7.
Mult Scler ; 16(10): 1203-12, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20699284

RESUMO

BACKGROUND: Neocortical lesions (NLs) largely contribute to the pathology of multiple sclerosis (MS), although their relevance in patients' disability remains unknown. OBJECTIVE: To assess the incidence of T(1) hypointense NLs by 3.0-Tesla magnetic resonance imaging (MRI) in patients with MS and examine neocortical lesion association with cognitive impairment. METHODS: In this case-control study, 21 MS patients and 21 age-, sex- and years of education-matched healthy volunteers underwent: (i) a neuropsychological examination rating cognitive impairment (Minimal Assessment of Cognitive Function in MS); (ii) a 3.0-Tesla MRI inclusive of an isotropic 1.0 mm(3) three-dimensional inversion prepared spoiled gradient-recalled-echo (3D-IRSPGR) image and T(1)- and T(2)-weighted images. Hypointensities on 3D-IRSPGR lying in the cortex, either entirely or partially were counted and association between NLs and cognitive impairment investigated. RESULTS: A total of 95 NLs were observed in 14 (66.7%) patients. NL+ patients performed poorer (p = 0.020) than NL-patients only on the delayed recall component of the California Verbal Learning Test. This difference lost statistical significance when a correction for white matter lesion volume was employed. CONCLUSIONS: Although T( 1) hypointense NLs may be present in a relatively high proportion of multiple sclerosis patients, the impact that they have in cognitive impairment is not independent from white matter disease.


Assuntos
Córtex Cerebral/patologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/psicologia , Esclerose Múltipla/patologia , Esclerose Múltipla/psicologia , Adulto , Estudos de Casos e Controles , Transtornos Cognitivos/etiologia , Avaliação da Deficiência , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Testes Neuropsicológicos , Aprendizagem Verbal/fisiologia , Adulto Jovem
8.
J Immunol ; 181(8): 5462-72, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18832703

RESUMO

Myelin basic protein (MBP)-specific T cells are thought to play a role in the development of multiple sclerosis. MBP residues 111-129 compose an immunodominant epitope cluster restricted by HLA-DRB1*0401. The sequence of residues 111-129 of MBP (MBP(111-129)) differs in humans (MBP122:Arg) and mice (MBP122:Lys) at aa 122. We previously found that approximately 50% of human MBP(111-129) (MBP122:Arg)-specific T cell clones, including MS2-3C8 can proliferate in response to mouse MBP(111-129) (MBP122:Lys). However, the other half of T cell clones, including HD4-1C2, cannot proliferate in response to MBP(111-129) (MBP122:Lys). We found that MBP(111-129) (MBP122:Lys) is an antagonist for HD4-1C2 TCR, therefore, MS2-3C8 and HD4-1C2 TCRs are agonist- and antagonist-specific TCRs in mice, respectively. Therefore, we examined the development of HD4-1C2 TCR and MS2-3C8 TCR transgenic (Tg) T cells in the thymus and periphery. We found that dual TCR expression exclusively facilitates the development of MBP(111-129) TCR Tg T cells in the periphery of HD4-1C2 TCR/HLA-DRB1*0401 Tg mice although it is not required for their development in the thymus. We also found that MS2-3C8 TCR Tg CD8(+) T cells develop along with MS2-3C8 TCR Tg CD4(+) T cells, and that dual TCR expression was crucial for the development of MS2-3C8 TCR Tg CD4(+) and CD8(+) T cells in the thymus and periphery, respectively. These results suggest that thymic and peripheral development of MBP-specific T cells are different; however, dual TCR expression can facilitate their development.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-DR/imunologia , Esclerose Múltipla/imunologia , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/antagonistas & inibidores , Peptídeos/farmacologia , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Transcrição/agonistas , Fatores de Transcrição/antagonistas & inibidores , Animais , Epitopos de Linfócito T/genética , Expressão Gênica/genética , Expressão Gênica/imunologia , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/genética , Proteína Básica da Mielina , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/genética , Timo/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
9.
Mult Scler ; 15(10): 1206-14, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19776093

RESUMO

Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/uso terapêutico , Rolipram/uso terapêutico , Biomarcadores/metabolismo , Barreira Hematoencefálica/patologia , Proliferação de Células/efeitos dos fármacos , Meios de Contraste , Humanos , Imunofenotipagem , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Inflamação/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Inibidores de Fosfodiesterase/efeitos adversos , Rolipram/efeitos adversos , Linfócitos T/patologia , Fatores de Tempo , Falha de Tratamento
12.
J Neuroimaging ; 26(3): 296-302, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26686343

RESUMO

BACKGROUND/PURPOSE: Contrast-enhancing lesions (CEL) on magnetic resonance imaging (MRI) are believed to represent inflammatory disease activity in multiple sclerosis (MS), but their relationship to subsequent long-term disability and progression is unclear, particularly at longer time periods such as 8-10 years. METHODS: Between 1989 and 1994, 111 MS patients were seen at the National Institutes of Health for clinical evaluations and 3 monthly contrast-enhanced MRI scans. Of these, 94 patients were re-evaluated a mean of 8 years later (range 6.1-10.5 years) with a single MRI scan and clinical evaluation. CEL number and volume were determined at baseline and follow-up. The number of relapses was ascertained over the follow-up period and annualized relapse rates were calculated. Other MRI parameters, such as T2 hyperintensity volume, T1 volume, and brain parenchymal fraction, were also calculated. RESULTS: While there was no direct correlation between CEL number or volume at baseline and disability status at follow-up, CEL measures at baseline did correlate with number of relapses observed in the subsequent years, and the number of relapses in turn correlated with subsequent disability as well as transition to progressive MS. CONCLUSION: While number and volume of CEL at baseline do not directly correlate with disability in the longer term in MS, our data suggest that 1 route to disability involves relapses as a mediator variable in the causal sequence of MS progression from CEL to disability. Further studies using relapse as a mediator variable in a larger data set may be warranted.


Assuntos
Avaliação da Deficiência , Aumento da Imagem , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Estatística como Assunto
13.
Nat Rev Neurol ; 12(12): 714-722, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27834394

RESUMO

Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.


Assuntos
Veias Cerebrais/diagnóstico por imagem , Consenso , Imageamento por Ressonância Magnética , Esclerose Múltipla/diagnóstico por imagem , Guias de Prática Clínica como Assunto/normas , Sociedades Médicas/normas , Humanos
14.
Arch Neurol ; 62(11): 1684-8, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16157739

RESUMO

BACKGROUND: Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. OBJECTIVE: To analyze the effects of interferon beta-1b in reducing the duration of T1 BHs in patients with multiple sclerosis. DESIGN: Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen. SETTING: Outpatient service of the Neuroimmunology Branch at the National Institutes of Health, Bethesda, Md. PATIENTS: Six patients with relapsing-remitting multiple sclerosis were included. One patient did not form any BHs during the therapy phase. Analyses were performed on the remaining 5 individuals. INTERVENTIONS: Interferon beta-1b at the dosage of 8 million international units every other day. MAIN OUTCOME MEASURES: Number and duration (in months) of newly formed BHs. RESULTS: Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (chi2(1) = 2.47, P = .12). CONCLUSIONS: Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Adulto , Distribuição de Qui-Quadrado , Humanos , Interferon beta-1b , Estudos Longitudinais , Imageamento por Ressonância Magnética/métodos , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
15.
Brain ; 127(Pt 11): 2506-17, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15456705

RESUMO

Cortical reorganization has been demonstrated in the motor network that mediates performance of a motor task in patients with multiple sclerosis. How this network responds to motor training is not known. This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements, before and after motor training in a group of multiple sclerosis patients with mild motor impairment of the right upper extremity. Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analysed using random effects analysis (SPM99). Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand. Before training, thumb movements elicited more prominent activation of the contralateral dorsal premotor cortex [PMd, Brodmann area (BA) 6] in multiple sclerosis patients than in controls. After training, unlike the control group, multiple sclerosis patients did not exhibit task-specific reductions in activation in the contralateral primary somatosensory (S1), motor (M1) and adjacent parietal association (BA 40) cortices. These results indicate that patients engage the contralateral PMd more than controls in order to perform directionally specific movements before training. The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the motor network with practice.


Assuntos
Esclerose Múltipla/reabilitação , Plasticidade Neuronal , Desempenho Psicomotor , Adulto , Fenômenos Biomecânicos , Mapeamento Encefálico , Eletromiografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Córtex Motor/fisiopatologia , Esclerose Múltipla/fisiopatologia , Polegar/fisiopatologia
17.
J Neuroimmunol ; 82(1): 96-100, 1998 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-9526851

RESUMO

An autoimmune T-cell response to myelin proteins is thought to be involved in the pathogenesis of multiple sclerosis (MS) and myelin basic protein (MBP) is the most widely studied potential target antigen. We investigated the T-cell response to MBP in MS patients and controls using two different molecular forms of the protein: the classical hydrophilic MBP (lipid-free MBP, LF-MBP) and a lipid-bound, native-like preparation of MBP isolated in a molecular form retaining the binding to all myelin lipids (lipid-bound-MBP, LB-MBP). Short term T-cell lines (TCL) were generated using either LF- or LB-MBP and tested for their reactivity to the in vitro stimulating antigen. No differences were detected between MS patients and healthy donors in the percentage of T-cell cultures responsive to the LF-MBP. In contrast, the number of LB-MBP reactive cultures was higher in MS patients than in controls. This difference was almost entirely due to the presence of high numbers of LB-MBP-specific TCL in MS patients which did not cross-react with LF-MBP and were not present in healthy subjects. LB-MBP may represent a novel antigen worth to be investigated in MS.


Assuntos
Esclerose Múltipla/imunologia , Proteína Básica da Mielina/imunologia , Linfócitos T/imunologia , Linhagem Celular , Reações Cruzadas , Humanos , Metabolismo dos Lipídeos , Lipídeos/imunologia , Proteína Básica da Mielina/metabolismo , Linfócitos T/citologia
18.
J Neuroimmunol ; 151(1-2): 94-102, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15145608

RESUMO

Since myelin basic protein (MBP)111-129 is an immunodominant epitope in humans carrying HLA-DRB1*0401, we investigated the encephalitogenic potential of HLA-DRB1*0401-restricted MBP111-129-specific T cells using HLA-DRB1*0401/DRA*0101 transgenic (Tg) mice. Although we could not detect the primary recall response to MBP111-129 peptide after immunization of HLA-DRB1*0401/DRA*0101 Tg mice with human MBP, V beta 10(+) and V beta 2(+) HLA-DRB1*0401-restricted MBP111-129-specific T cells proliferated after restimulation of the lymph node cells with human MBP111-129 in vitro. The V beta 2(+) T cell line recognized only human MBP111-129 in the context of HLA-DRB1*0401, while the V beta 10(+) T cell line recognized both the human and murine MBP111-129 epitopes. Therefore, we examined the encephalitogenic potential of the V beta 10(+) T cell line in HLA-DRB1*0401/DRA*0101 Tg mice by adoptive transfer experiments. The V beta 10(+) T cell line induced mild EAE and inflammatory lesions were observed in the spinal cord and the brainstem. In the spinal cord, the inflammation was observed in the peripheral nerve roots as well as in the CNS. These data suggest the pathogenic potential of HLA-DRB1*0401-restricted MBP111-129-specific T cells in humans.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Antígenos HLA-DR/imunologia , Proteína Básica da Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Sequência de Aminoácidos , Animais , Sequência de Bases , Linhagem Celular , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Epitopos de Linfócito T , Citometria de Fluxo , Cadeias HLA-DRB1 , Humanos , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
19.
Semin Arthritis Rheum ; 34(3): 623-30, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15609267

RESUMO

OBJECTIVES: To examine the frequency of central nervous system (CNS) disease in primary Sjogrens syndrome (pSS) and indicate ways in which cerebral magnetic resonance imaging (MRI) may help determine the significance of CNS involvement. METHODS: The current review was based on a Medline (Pubmed) literature search through May 2003, focused on Sjogrens syndrome, other vasculitides, multiple sclerosis (MS), specific MRI techniques, and MRI findings with regard to the above-mentioned diseases. Additional literature was identified in the reference sections of articles listed in Medline. RESULTS: Severe CNS manifestations reminiscent of MS have been described in pSS patients. Moreover, the prevalence of nonfocal neuropsychological abnormalities has been found to be elevated in some pSS patient populations. MRI studies suggest discrete cerebral tissue damage even in neurologically asymptomatic patients. However, small white matter lesions are nonspecific and may be related to age or cerebrovascular risk factors such as hypertension. A large controlled study, complementing established T2-weighted MRI with fluid-attenuated inversion recovery (FLAIR) to achieve high sensitivity in lesion detection, could indicate the disease specificity of white matter lesions in pSS. Newer MR techniques, such as spectroscopy and magnetization transfer imaging, applied, for example, in MS and systemic lupus erythematosus (SLE) to evaluate CNS tissue injury, could help determine the extent and mechanisms of macroscopic and microscopic CNS lesions in pSS. CONCLUSIONS: Future controlled studies will be necessary to more precisely estimate the prevalence of CNS lesions in pSS, specifically of discrete white matter abnormalities. Newer MRI techniques have the potential to provide information on the severity and pathophysiological mechanisms of CNS tissue damage.


Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética , Esclerose Múltipla/complicações , Síndrome de Sjogren/complicações , Humanos , MEDLINE , Esclerose Múltipla/patologia , Síndrome de Sjogren/patologia
20.
Neurology ; 80(5): 453-7, 2013 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-23303850

RESUMO

OBJECTIVE: To report the development of CNS vasculitis in a patient with multiple sclerosis (MS) treated with daclizumab. METHODS: This report includes clinical, MRI, immunologic, and pathology data and CSF analysis. RESULTS: After completing a phase II daclizumab monotherapy study with an optimal response as evidenced by significant decrease in MRI disease activity and stable clinical examinations, the patient elected to continue daclizumab therapy outside of NIH study. Daclizumab was discontinued after 21 doses due to the onset of new clinical symptoms and evidence of a vascular pattern of contrast enhancement on brain and spine MRI. Because of continued clinical deterioration, stereotactic brain biopsy was performed, showing small-vessel CNS vasculitis. Treatment was initiated with IV methylprednisolone followed by a regimen of cyclophosphamide. Immunologic studies suggest that unexpected lack of expansion of CD56(bright) NK cells and predictable decline in FoxP3+ T-regs combined with a transient interruption in daclizumab dosing may have contributed to this serious side effect. CONCLUSIONS: Only safety data from larger phase III studies and potentially postmarketing experience will define the exact risk of daclizumab-induced immunopathologies. Nevertheless, our case provides plausible hypothesis and potential biomarker that may be used to screen susceptible patients and implement preventive safety measures during potentially vulnerable periods.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/complicações , Vasculite do Sistema Nervoso Central/tratamento farmacológico , Vasculite do Sistema Nervoso Central/etiologia , Anti-Inflamatórios/uso terapêutico , Antígeno CD56/metabolismo , Ciclofosfamida/uso terapêutico , Daclizumabe , Avaliação da Deficiência , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Imageamento por Ressonância Magnética , Masculino , Metilprednisolona/uso terapêutico , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico , Vasculite do Sistema Nervoso Central/patologia
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