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Multiple Sclerosis 05/2013; 19(6):717-8. · 4.26 Impact Factor
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ABSTRACT: In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNβ)-1a in patients with relapsing-remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFNβ-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFNβ-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32-59 % relative to IFNβ-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNβ-1a in most (95 %) subgroups. In patients with high disease activity despite IFNβ treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNβ-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFNβ-1a across different subgroups of patients with RRMS.
Journal of Neurology 04/2013; · 3.47 Impact Factor
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Mirja Wallner-Blazek,
Alex Rovira,
Massimo Fillipp,
Mara A Rocca,
David H Miller,
Klaus Schmierer,
Jette Frederiksen,
Achim Gass,
Hugo Gama,
Charles P Tilbery,
Antonio J Rocha,
José Flores,
Frederik Barkhof,
Alexandra Seewann,
Jacqueline Palace,
Tarek Yousry, Xavier Montalban,
Christian Enzinger,
Franz Fazekas
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ABSTRACT: Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can be classified according to previously suggested radiologic characteristics and how this classification relates to prognosis. Searching the databases of eight tertiary referral centres we identified 90 adult patients (61 women, 29 men; mean age 34 years) with ≥1 AIIDL. We collected their demographic, clinical and magnetic resonance imaging data and obtained follow-up (FU) information on 77 of these patients over a mean duration of 4 years. The AIIDLs presented as a single lesion in 72 (80 %) patients and exhibited an infiltrative (n = 35), megacystic (n = 16), Baló (n = 10) or ring-like (n = 16) lesion appearance in 77 (86 %) patients. Additional multiple sclerosis (MS)-typical lesions existed in 48 (53 %) patients. During FU, a further clinical attack occurred rarely (23-35 % of patients) except for patients with ring-like AIIDLs (62 %). Further attacks were also significantly more often in patients with coexisting MS-typical lesions (41 vs. 10 %, p < 0.005). New AIIDLs developed in six (7 %), and new MS-typical lesions in 29 (42 %) patients. Our findings confirm the previously reported subtypes of AIIDLs. Most types confer a relatively low risk of further clinical attacks, except for ring-like lesions and the combination with MS-typical lesions.
Journal of Neurology 04/2013; · 3.47 Impact Factor
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Manuel Comabella,
Ana B Caminero,
Sunny Malhotra,
Luis Agulló,
Oscar Fernández,
Ferran Reverter,
Koen Vandenbroeck,
Alfredo Rodríguez-Antigüedad,
Fuencisla Matesanz,
Guillermo Izquierdo,
Elena Urcelay,
Arturo López-Larios,
Alex Sánchez,
Susana Otero,
Mar Tintoré, Xavier Montalban
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ABSTRACT: OBJECTIVES: To investigate the roles of 2 polymorphisms of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene, rs1800693 (a common variant) and rs4149584 (a coding polymorphism that results in an amino acid substitution-R92Q), as genetic modifiers of multiple sclerosis (MS), and to evaluate their potential functional implications in the disease. METHODS: The effects of rs1800693 and rs4149584 on 2 measures of disease severity, age at disease onset and Multiple Sclerosis Severity Score, were analyzed in 2,032 patients with MS. In a subgroup of patients, serum levels of the soluble form of TNF-R1 (sTNF-R1) were measured by ELISA; mRNA expression levels of the full-length TNF-R1 and 6-TNF-R1 isoform were investigated in peripheral blood mononuclear cells (PBMC) by real-time PCR; cell surface expression of the TNF-R1 was determined in T cells by flow cytometry. RESULTS: For rs4149584, R92Q carriers were younger at disease onset and progressed slower compared to noncarriers. However, no association with disease severity was observed for rs1800693. Serum levels of sTNF-R1 and mRNA expression levels of the full-length receptor were significantly increased in patients with MS carrying the R92Q mutation (p = 0.003 and p = 0.011, respectively), but similarly distributed among rs1800693 genotypes; cell surface TNF-R1 expression in T cells did not differ between rs4149584 and rs1800693 genotypes. The truncated soluble 6-TNF-R1 isoform was identified in PBMC from patients carrying the risk allele for rs1800693. CONCLUSIONS: These findings suggest that both rs1800693 and rs4149584 TNFRSF1A polymorphisms have functional consequences in the TNF-R1.
Neurology 04/2013; · 8.31 Impact Factor
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Medicina Clínica 04/2013; · 1.38 Impact Factor
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Ralf Gold,
Gavin Giovannoni,
Krzysztof Selmaj,
Eva Havrdova, Xavier Montalban,
Ernst-Wilhelm Radue,
Dusan Stefoski,
Randy Robinson,
Katherine Riester,
Jitesh Rana,
Jacob Elkins,
Gilmore O'Neill
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ABSTRACT: BACKGROUND: Daclizumab, a humanised monoclonal antibody, modulates interleukin-2 signalling by blocking the α subunit (CD25) of the interleukin-2 receptor. We assessed whether daclizumab high-yield process (HYP) would be effective when given as monotherapy for a 1 year treatment period in patients with relapsing-remitting multiple sclerosis. METHODS: We did a randomised, double-blind, placebo-controlled trial at 76 centres in the Czech Republic, Germany, Hungary, India, Poland, Russia, Ukraine, Turkey, and the UK between Feb 15, 2008, and May 14, 2010. Patients aged 18-55 years with relapsing-remitting multiple sclerosis were randomly assigned (1:1:1), via a central interactive voice response system, to subcutaneous injections of daclizumab HYP 150 mg or 300 mg, or placebo, every 4 weeks for 52 weeks. Patients and study personnel were masked to treatment assignment, except for the site pharmacist who prepared the study drug for injection, but had no interaction with the patient. The primary endpoint was annualised relapse rate. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00390221. FINDINGS: 204 patients were assigned to receive placebo, 208 to daclizumab HYP 150 mg, and 209 to daclizumab HYP 300 mg, of whom 188 (92%), 192 (92%), and 197 (94%), respectively, completed follow-up to week 52. The annualised relapse rate was lower for patients given daclizumab HYP 150 mg (0·21, 95% CI 0·16-0·29; 54% reduction, 95% CI 33-68%; p<0·0001) or 300 mg (0·23, 0·17-0·31, 50% reduction, 28-65%; p=0·00015) than for those given placebo (0·46, 0·37-0·57). More patients were relapse free in the daclizumab HYP 150 mg (81%) and 300 mg (80%) groups than in the placebo group (64%; p<0·0001 in the 150 mg group and p=0·0003 in the 300 mg group). 12 (6%) patients in the placebo group, 15 (7%) of those in the daclizumab 150 mg group, and 19 (9%) in the 300 mg group had serious adverse events excluding multiple sclerosis relapse. One patient given daclizumab HYP 150 mg who was recovering from a serious rash died because of local complication of a psoas abscess. INTERPRETATION: Subcutaneous daclizumab HYP administered every 4 weeks led to clinically important effects on multiple sclerosis disease activity during 1 year of treatment. Our findings support the potential for daclizumab HYP to offer an additional treatment option for relapsing-remitting disease. FUNDING: Biogen Idec and AbbVie Biotherapeutics Inc.
The Lancet 04/2013; · 38.28 Impact Factor
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Veronica Popescu,
Federica Agosta,
Hanneke E Hulst,
Ingrid C Sluimer,
Dirk L Knol,
Maria Pia Sormani,
Christian Enzinger,
Stefan Ropele,
Julio Alonso,
Jaume Sastre-Garriga, [......],
Nicola De Stefano,
Philipp Eisele,
Achim Gass,
Chris H Polman,
Bernard M J Uitdehaag,
Maria Jose Messina,
Giancarlo Comi,
Massimo Filippi,
Frederik Barkhof,
Hugo Vrenken
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ABSTRACT: OBJECTIVE: To determine whether brain atrophy and lesion volumes predict subsequent 10 year clinical evolution in multiple sclerosis (MS). DESIGN: From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MS patients with MR imaging at baseline and after 1-2 years, and Expanded Disability Status Scale (EDSS) scoring at baseline and after 10 years. Annualised whole brain atrophy, central brain atrophy rates and T2 lesion volumes were calculated. Patients were categorised by baseline diagnosis as primary progressive MS (n=77), clinically isolated syndromes (n=18), relapsing-remitting MS (n=97) and secondary progressive MS (n=69). Relapse onset patients were classified as minimally impaired (EDSS=0-3.5, n=111) or moderately impaired (EDSS=4-6, n=55) according to their baseline disability (and regardless of disease type). Linear regression models tested whether whole brain and central atrophy, lesion volumes at baseline, follow-up and lesion volume change predicted 10 year EDSS and MS Severity Scale scores. RESULTS: In the whole patient group, whole brain and central atrophy predicted EDSS at 10 years, corrected for imaging protocol, baseline EDSS and disease modifying treatment. The combined model with central atrophy and lesion volume change as MRI predictors predicted 10 year EDSS with R(2)=0.74 in the whole group and R(2)=0.72 in the relapse onset group. In subgroups, central atrophy was predictive in the minimally impaired relapse onset patients (R(2)=0.68), lesion volumes in moderately impaired relapse onset patients (R(2)=0.21) and whole brain atrophy in primary progressive MS (R(2)=0.34). CONCLUSIONS: This large multicentre study points to the complementary predictive value of atrophy and lesion volumes for predicting long term disability in MS.
Journal of neurology, neurosurgery, and psychiatry 03/2013; · 4.87 Impact Factor
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ABSTRACT: Notch is a family of receptors involved in the differentiation of several tissues, including the central nervous system and the immune system. One of the Notch ligands, Delta-like 4 (Dll4), has been implicated in the differentiation of Th1 cells and the development of Th17 responses, which are involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis. Our results show that a single administration of an anti-Dll4 antibody is not enough to avoid the development of EAE or to ameliorate the already established clinical signs, despite the treatment reduces the proliferative T cell responses and decreases Th1/Th17 immune responses.
Neuroscience Letters 03/2013; · 2.11 Impact Factor
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ABSTRACT: Semaphorins have been classically defined as axonal signalling cues involved in central nervous system (CNS) development, but in adults these molecules are expressed in distinct tissues and exert various functions under several physiological and pathological contexts. Semaphorins capable of modulating the immune system are particularly relevant in autoimmune diseases, especially multiple sclerosis (MS), which is a demyelinating, neurodegenerative disease. In this article, we compile recent insights into the specific roles of semaphorin (sema)3A and sema7A to clarify the details of their possible participation in the inflammatory and neurodegenerative phases of MS.
Trends in Molecular Medicine 02/2013; · 10.35 Impact Factor
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Angela Vidal-Jordana,
Jaume Sastre-Garriga,
Francisco Pérez-Miralles,
Carmen Tur,
Mar Tintoré,
Alejandro Horga,
Cristina Auger,
Jordi Río,
Carlos Nos,
Mari C Edo,
María J Arévalo,
Joaquín Castilló,
Alex Rovira, Xavier Montalban
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ABSTRACT: BACKGROUND: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. OBJECTIVE: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. METHODS: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. RESULTS: The PBVC decrease was faster during the first year (-1.10% ± 1.43%), as compared to the second (-0.51% ± 0.96%) (p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions (p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and -1.72% (p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC (p = 0.022) and WMF change (p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. CONCLUSION: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.
Multiple Sclerosis 01/2013; · 4.26 Impact Factor
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Christina M Lill,
Brit-Maren M Schjeide,
Christiane Graetz,
Tian Liu,
Vincent Damotte,
Denis A Akkad,
Paul Blaschke,
Lisa-Ann Gerdes,
Antje Kroner,
Felix Luessi, [......],
Peter Lohse,
Mathias Buttmann,
Tania Kümpfel,
Christian Kubisch,
Uwe K Zettl,
Joerg T Epplen,
Bertrand Fontaine,
Frauke Zipp,
Koen Vandenbroeck,
Lars Bertram
Journal of Medical Genetics 01/2013; · 6.36 Impact Factor
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ABSTRACT: Anti-glycan antibodies can be found in autoimmune diseases. IgM against glycan P63 was identified in clinically isolated syndromes (CIS) and included in gMS-Classifier2, an algorithm designed with the aim of identifying patients at risk of a second demyelinating attack.
To determine the value of gMS-Classifier2 as an early and independent predictor of conversion to clinically definite multiple sclerosis (CDMS).
Data were prospectively acquired from a CIS cohort. gMS-Classifier2 was determined in patients first seen between 1995 and 2007 with ≥ two 200 µL serum aliquots (N = 249). The primary endpoint was time to conversion to CDMS at two years, the factor tested was gMS-Classifier2 status (positive/negative) or units; other exploratory time points were 5 years and total time of follow-up.
Seventy-five patients (30.1%) were gMS-Classifier2 positive. Conversion to CDMS occurred in 31/75 (41.3%) of positive and 45/174 (25.9%) of negative patients (p = 0.017) at two years. Median time to CDMS was 37.8 months (95% CI 10.4-65.3) for positive and 83.9 months (95% CI 57.5-110.5) for negative patients. gMS-Classifier2 status predicted conversion to CDMS within two years of follow-up (HR = 1.8, 95% CI 1.1-2.8; p = 0.014). gMS-Classifier2 units were also independent predictors when tested with either Barkhof criteria and OCB (HR = 1.2, CI 1.0-1.5, p = 0.020) or with T2 lesions and OCB (HR = 1.3, CI 1.1-1.5, p = 0.008). Similar results were obtained at 5 years of follow-up. Discrimination measures showed a significant change in the area under the curve (ΔAUC) when adding gMS-Classifier2 to a model with either Barkhof criteria (ΔAUC 0.0415, p = 0.012) or number of T2 lesions (ΔAUC 0.0467, p = 0.009), but not when OCB were added to these models.
gMS-Classifier2 is an independent predictor of early conversion to CDMS and could be of clinical relevance, particularly in cases in which OCB are not available.
PLoS ONE 01/2013; 8(3):e59953. · 4.09 Impact Factor
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ABSTRACT: A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment.
Twenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays.
Purified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb.
PLoS ONE 01/2013; 8(4):e60994. · 4.09 Impact Factor
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Esther Byun,
Stacy J Caillier, Xavier Montalban,
Pablo Villoslada,
Oscar Fernández,
David Brassat,
Manuel Comabella,
Joanne Wang,
Lisa F Barcellos,
Sergio E Baranzini,
Jorge R Oksenberg
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Giancarlo Comi,
Vittorio Martinelli,
Mariaemma Rodegher,
Lucia Moiola,
Letizia Leocani,
Ovidiu Bajenaru,
Adriana Carra,
Irina Elovaara,
Franz Fazekas,
Hans-Peter Hartung, [......],
Catherine Lubetzki, Xavier Montalban,
Kjell-Morten Myhr,
Paolo Preziosa,
Mads Ravnborg,
Peter Rieckmann,
Maria A Rocca,
Daniel Wynn,
Carolyn Young,
Massimo Filippi
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ABSTRACT: BACKGROUND: The placebo-controlled phase of the PreCISe study showed that glatiramer acetate delayed onset of clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome and brain lesions on MRI. OBJECTIVE: To compare the effects of early versus delayed glatiramer acetate treatment in the open-label phase of PreCISe. METHODS: Patients with a clinically isolated syndrome suggestive of MS with unifocal manifestation and ≥2 T2-weighted brain lesions were randomized to receive glatiramer acetate 20 mg/d (early-treatment, n=198) or placebo (delayed-treatment, n=211) for 36 months or until conversion to CDMS, followed by open-label glatiramer acetate treatment for two years. RESULTS: Early glatiramer acetate treatment reduced CDMS conversion risk by 41% (hazard ratio 0.59, 95% confidence interval 0.44-0.80; p=0.0005) versus delayed-treatment, and was associated with a 972-day delay (185%) in conversion to CDMS, less brain atrophy (-28%, p=0.0209), fewer new T2 lesions/year (-42%, <0.0001) and lower T2 lesion volume (-22%, p=0.0005) versus delayed treatment. Adverse events were consistent with the established safety profile of glatiramer acetate. CONCLUSIONS: Effects of early glatiramer acetate treatment on the rate of conversion to CDMS and on MRI measures of disease activity and lesion burden support initiating glatiramer acetate treatment soon after the first clinical symptoms suggestive of MS and continuing treatment to sustain benefits.
Multiple Sclerosis 12/2012; · 4.26 Impact Factor
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Alba Gomez,
Carmen Espejo,
Herena Eixarch,
Silvia Casacuberta-Serra,
Maria Jose Mansilla,
Rebeca Sanchez,
Sonia Pereira,
Sergio Lopez-Estévez,
Ramon Gimeno, Xavier Montalban,
Jordi Barquinero
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ABSTRACT: Previous work by our group showed that transferring bone marrow cells transduced with an autoantigen into non-myeloablated mice with experimental autoimmune encephalomyelitis induced immune tolerance and improved the disease. Since this effect occurred in the absence of molecular chimerism, we hypothesized that the cells responsible did not have repopulating ability and that they were not mediating central but peripheral tolerance mechanisms. In the present study, we analyzed the immunophenotype of the cells that are generated in the transduction cultures and we evaluated the immunosuppressive activity of the main cell subpopulations produced. We show that both granulocytic (CD11b⁺ Gr-1(hi)) and monocytic (CD11b⁺ Gr-1(lo)) myeloid-derived suppressor cells (G- and M-MDSCs, respectively) are generated during standard four-day gamma-retroviral transduction cultures (representing about 25 and 40% of the total cell output, respectively) and that the effectively transduced cells largely consist of these two cell types. A third cell population representing about 15% of the transduced cells did not express CD45 or hematopoietic lineage markers, and expressed mesenchymal stromal cell markers. Transduced total bone marrow cells and sorted M-MDSCs expressed arginase and inducible nitric oxide synthase activities, produced reactive oxygen species, and inhibited antigen-induced T cell proliferation in vitro. Transgene-expressing MDSCs could be exploited therapeutically to induce tolerance in autoimmune diseases and in gene therapy protocols.
Cell Transplantation 11/2012; · 5.13 Impact Factor
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ABSTRACT: Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.
Journal of Neurology 11/2012; · 3.47 Impact Factor
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Antonio Alcina,
Maria Fedetz,
Oscar Fernández,
Albert Saiz,
Guillermo Izquierdo,
Miguel Lucas,
Laura Leyva,
Juan-Antonio García-León,
María Del Mar Abad-Grau,
Iraide Alloza, [......],
Rafael Arroyo,
Manuel Comabella, Xavier Montalban,
Natalia Petit-Marty,
Arcadi Navarro,
David Otaegui,
Javier Olascoaga,
Yolanda Blanco,
Elena Urcelay,
Fuencisla Matesanz
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ABSTRACT: BACKGROUND AND AIM: Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS. METHODS: Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses. RESULTS: rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously. CONCLUSIONS: This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.
Journal of Medical Genetics 11/2012; · 6.36 Impact Factor
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Expert Review of Clinical Immunology 07/2012; 8(5):423-6. · 2.07 Impact Factor
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ABSTRACT: DNA vaccines represent promising therapeutic strategies in autoimmune disorders such as multiple sclerosis (MS). However, the precise mechanisms by which DNA vaccines induce immune regulation remain largely unknown. Here, we aimed to expand previous knowledge existing on the mechanisms of action of DNA vaccines in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), by treating EAE mice with a DNA vaccine encoding the myelin oligodendrocyte glycoprotein (MOG), and exploring the therapeutic effects on the disease-induced inflammatory and neurodegenerative changes.
EAE was induced in C57BL6/J mice by immunization with MOG₃₅₋₅₅ peptide. Mice were intramuscularly treated with a MOG-DNA vaccine or vehicle in prophylactic and therapeutic approaches. Histological studies were performed in central nervous system (CNS) tissue. Cytokine production and regulatory T cell (Treg) quantification were achieved by flow cytometry. Gene expression patterns were determined using microarrays, and the main findings were validated by real-time PCR.
MOG-DNA treatment reduced the clinical and histopathological signs of EAE when administered in both prophylactic and therapeutic settings. Suppression of clinical EAE was associated with dampening of antigen (Ag)-specific proinflammatory Th1 and Th17 immune responses and, interestingly, expansion of Treg in the periphery and upregulation in the CNS of genes encoding neurotrophic factors and proteins involved in remyelination.
These results suggest for the first time that the beneficial effects of DNA vaccines in EAE are not limited to anti-inflammatory mechanisms, and DNA vaccines may also exert positive effects through hitherto unknown neuroprotective mechanisms.
Journal of Neuroinflammation 06/2012; 9:139. · 3.83 Impact Factor
