Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 45
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
JAMA Neurol ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31589278

RESUMO

Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden. Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS. Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included. Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon beta and GA. Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions. Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]). Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.

2.
J Interferon Cytokine Res ; 39(5): 302-313, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30848986

RESUMO

Interferon beta (IFNß) is used as a first-line treatment for multiple sclerosis (MS) and is injected intramuscularly or subcutaneously (s.c.). The subcutaneous route is considered more immunogenic as it is associated with increased antidrug antibody-positive patients. The skin contains dendritic cells (DCs) and it is unclear whether these contribute to immunogenicity. To assess the effect of IFNß on skin-resident cells, IFNß was injected intradermally (i.d.) ex vivo using a human skin explant model or s.c. in vivo in MS patients. Ex vivo, intradermal IFNß injections reduced migration and enhanced surface CD86 expression of dermal DCs, and an increased expression of HLA-DR+ was observed in skin biopsies taken after subcutaneous IFNß injection (in vivo). In both models, IFNß elevated the expression of several inflammatory cytokines when compared to the control biopsies. Our results show that 3 different IFNß preparations, normalized in dose and injection site, induce similar immune responses, suggesting that the differences in immunogenicity are likely due to the route and frequency of administration.

4.
J Neuroimmunol ; 326: 19-27, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30447419

RESUMO

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-ß) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-ß-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-ß ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30420245

RESUMO

OBJECTIVES: To evaluate the incidence of anti-drug antibody (ADA) occurrences and ADA-related risk factors under adalimumab and infliximab treatment in rheumatoid arthritis (RA) patients. METHODS: The study combined retrospective cohorts from the ABIRISK project totaling 366 RA patients treated with adalimumab (n = 240) or infliximab (n = 126), 92.4% of them anti-TNF naive (n = 328/355) and 96.6% of them co-treated with methotrexate (n = 341/353) with up to 18 months follow-up. ADA positivity was measured by enzyme-linked immunosorbent assay. The cumulative incidence of ADA was estimated, and potential bio-clinical factors were investigated using a Cox regression model on interval-censored data. RESULTS: ADAs were detected within 18 months in 19.2% (n = 46) of the adalimumab-treated patients and 29.4% (n = 37) of the infliximab-treated patients. The cumulative incidence of ADA increased over time. In the adalimumab and infliximab groups, respectively, the incidence was 15.4% (5.2-20.2) and 0% (0-5.9) at 3 months, 17.6% (11.4-26.4) and 0% (0-25.9) at 6 months, 17.7% (12.6-37.5) and 34.1% (11.4-46.3) at 12 months, 50.0% (25.9-87.5) and 37.5% (25.9-77.4) at 15 months and 50.0% (25.9-87.5) and 66.7% (37.7-100) at 18 months. Factors associated with a higher risk of ADA development were: longer disease duration (1-3 vs. < 1 year; adalimumab: HR 3.0, 95% CI 1.0-8.7; infliximab: HR 2.7, 95% CI 1.1-6.8), moderate disease activity (DAS28 3.2-5.1 vs. < 3.2; adalimumab: HR 6.6, 95% CI 1.3-33.7) and lifetime smoking (infliximab: HR 2.7, 95% CI 1.2-6.3). CONCLUSIONS: The current study focusing on patients co-treated with methotrexate for more than 95% of them found a late occurrence of ADAs not previously observed, whereby the risk continued to increase over 18 months. Disease duration, DAS28 and lifetime smoking are clinical predictors of ADA development.

6.
Virus Res ; 256: 134-141, 2018 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-30130603

RESUMO

BACKGROUND: Human herpesvirus 6B (HHV-6B) is a neurotropic virus that has been repeatedly associated with mesial temporal lobe epilepsy (MTLE). However, the mechanism behind this suggested association is not known. Therefore, the aim of this study was to investigate what genes were affected by HHV-6B, possibly revealing HHV-6B induced disease causing mechanisms. MATERIAL AND METHOD: First, gene expression in MTLE tissue positive for HHV-6B DNA (n = 10) and negative for HHV-6B DNA (n = 14) was compared using the Affymetrix® Human Gene 2.1 ST Array. Secondly, in vitro experiments were conducted where Molt-3 T cells were infected with HHV-6B and gene expression of MAP2K4 (MKK4) and 89 other genes in the MAPK signaling pathway was investigated using qPCR. In addition, phosphorylated MKK4 was assessed using IFA and the DNA methylation investigated with Illumina Infinium HumanMethylation450 BeadChip array. RESULTS: MAP2K4 was one of the most differently expressed genes in the Affymetrix array, suggesting an upregulation by HHV-6B infection in MTLE tissue. No gene reached statistical significance but MAP2K4 was selected for further investigation in vitro, where it was clearly upregulated by HHV-6B infection both on gene expression and protein expression level. Further investigating expression of genes in the MAPK pathways in vitro revealed that several genes were affected by HHV-6B infection, but none of these genes displayed viral induced changes in DNA methylation. CONCLUSIONS: As the MAPK pathways are involved in transforming different stimuli (like stress) into a cellular responses (like apoptosis or inflammation), it may not be surprising that genes in these pathways are affected by virus infection. This is the first report of HHV-6B's effect on these signaling cascades and given that both dysregulation of the MAPK pathways and an association with HHV-6B have been previously observed in epilepsy, a possible link of infection induced dysregulation of MAPK in epilepsy warrant further investigation.

7.
JCI Insight ; 3(11)2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29875313

RESUMO

Multiple sclerosis (MS) is an autoimmune disease characterized by CNS inflammation leading to demyelination and axonal damage. IFN-ß is an established treatment for MS; however, up to 30% of IFN-ß-treated MS patients develop neutralizing antidrug antibodies (nADA), leading to reduced drug bioactivity and efficacy. Mechanisms driving antidrug immunogenicity remain uncertain, and reliable biomarkers to predict immunogenicity development are lacking. Using high-throughput flow cytometry, NOTCH2 expression on CD14+ monocytes and increased frequency of proinflammatory monocyte subsets were identified as baseline predictors of nADA development in MS patients treated with IFN-ß. The association of this monocyte profile with nADA development was validated in 2 independent cross-sectional MS patient cohorts and a prospective cohort followed before and after IFN-ß administration. Reduced monocyte NOTCH2 expression in nADA+ MS patients was associated with NOTCH2 activation measured by increased expression of Notch-responsive genes, polarization of monocytes toward a nonclassical phenotype, and increased proinflammatory IL-6 production. NOTCH2 activation was T cell dependent and was only triggered in the presence of serum from nADA+ patients. Thus, nADA development was driven by a proinflammatory environment that triggered activation of the NOTCH2 signaling pathway prior to first IFN-ß administration.

8.
Mult Scler Int ; 2018: 5342936, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29682349

RESUMO

Multiple sclerosis (MS) is a heterogeneous disease which is poorly studied in Asia, where the disease is known to be rare with significant differences in clinical and radiological presentations and intrathecal antibody response. Therefore the objective of this study was to determine clinical presentation, radiological and neurophysiological characteristics, and oligoclonal band status in Sri Lankan MS patients, following careful exclusion of patients with neuromyelitis optica spectrum disorders and other conditions mimicking multiple sclerosis. Sixty-nine MS patients were recruited to the study adhering to McDonald 2010 criteria. Their clinical presentation, characteristics of central nervous system lesions in magnetic resonance imaging, visual evoked potential (VEP) results, oligoclonal bands (OCB), and AQP4 antibody status were studied. Of 69 MS patients, 54%, 6%, and 1% were relapsing remitting, secondary progressive, and primary progressive, respectively, and 39% were patients with clinically isolated syndrome. The commonest clinical presentations were cerebral motor followed by cerebral sensory and optic neuritis. Majority had typical periventricular and infratentorial lesions in MRI. Though not clinically apparent, bilateral delay of P100 wave latency was present in 52%. OCB positivity was 42% and AQP4 antibody was positive in only one patient. In conclusion, this group of Sri Lankan MS patients shares most of the clinical and radiological features of Caucasian MS patients. However, the OCB positivity is lower in this group, when compared to the Caucasian MS populations.

9.
Mult Scler ; : 1352458517753721, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29336205

RESUMO

BACKGROUND: Anti-drug antibodies (ADA) against natalizumab develop early during treatment. ADA persistency is defined by two consecutive positive results as performed by the current qualitative ELISA assay (positive/negative). Very little is known about the magnitude of the natalizumab ADA response and persistency. DESIGN/METHODS: We developed a highly sensitive natalizumab ADA titration assay on the Meso Scale Discovery (MSD) platform and a pharmacokinetic (PK) assay. We included 43 patients with a positive ELISA-ADA result within 6 months of treatment initiation (baseline) of whom a follow-up serum sample was available 12-30 months after treatment start. MSD-ADA titres and drug levels were measured. RESULTS: Median MSD-ADA titre at baseline was 4881 and 303 at follow-up. A titre of >400 at baseline had a 94% sensitivity and 89% specificity to predict ADA persistency. Reversion to ADA negativity occurred in 10 patients with mean drug levels of 10.8 µg/mL. The median trough drug level in ADA-positive samples was 0 µg/mL. PK levels and ADA titres correlated strongly negatively ( r = -0.67). CONCLUSION: High baseline natalizumab ADA titres accurately predict persistency. Despite continuous treatment, the majority of patients with persistent ADA had no detectable drug levels indicating loss of efficacy in line with phase 3 study results.

10.
Mult Scler ; 24(9): 1224-1233, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28762877

RESUMO

BACKGROUND: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown. OBJECTIVE: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients. METHODS: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house-validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records. RESULTS: ADAs were detected in 37% of relapsing-remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive. CONCLUSION: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.

11.
Front Neurol ; 8: 305, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28729851

RESUMO

OBJECTIVE: To develop and validate a method for the detection of binding anti-drug antibodies (ADAs) against interferon beta (IFN-ß) in human serum as part of a European initiative (ABIRISK) aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk. METHOD: A two-tiered bridging enzyme-linked immunosorbent assay (ELISA) format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-ß and biotinylated IFN-ß, which are then detected using HRP labeled Streptavidin and TMB substrate. Confirmation assay: Screen "putative positive" samples are tested in the presence of excess drug (preincubation of sera with 0.3 µg/mL of soluble IFN-ß) and percentage of inhibition is calculated. RESULTS: The assay is precise, and the sensitivity of the assay was confirmed to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-ß in human sera as the positive control. CONCLUSION: An ultrasensitive ELISA for IFN-ß-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-ß with regards to its clinical relevance and may allow for the development of predictive tools, key aims within the ABIRISK consortium.

12.
J Virol ; 91(11)2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28298607

RESUMO

Human herpesvirus 6B (HHV-6B) is a neurotropic betaherpesvirus that achieves latency by integrating its genome into host cell chromosomes. Several viruses can induce epigenetic modifications in their host cells, but no study has investigated the epigenetic modifications induced by HHV-6B. This study analyzed methylation with an Illumina 450K array, comparing HHV-6B-infected and uninfected Molt-3 T cells 3 days postinfection. Bisulfite pyrosequencing was used to validate the Illumina results and to investigate methylation over time in vitro Expression of genes was investigated using quantitative PCR (qPCR), and virus integration was investigated with PCR. A total of 406 CpG sites showed a significant HHV-6B-induced change in methylation in vitro Remarkably, 86% (351/406) of these CpGs were located <1 Mb from chromosomal ends and were all hypomethylated in virus-infected cells. This was most evident at chromosome 17p13.3, where HHV-6B had induced CpG hypomethylation after 2 days of infection, possibly through TET2, which was found to be upregulated by the virus. In addition, virus-induced cytosine hydroxymethylation was observed. Genes located in the hypomethylated region at 17p13.3 showed significantly upregulated expression in HHV-6B-infected cells. A temporal experiment revealed HHV-6B integration in Molt-3 cell DNA 3 days after infection. The telomere at 17p has repeatedly been described as an integration site for HHV-6B, and we show for the first time that HHV-6B induces hypomethylation in this region during acute infection, which may play a role in the integration process, possibly by making the DNA more accessible.IMPORTANCE The ability to establish latency in the host is a hallmark of herpesviruses, but the mechanisms differ. Human herpesvirus 6B (HHV-6B) is known to establish latency through integration of its genome into the telomeric regions of host cells, with the ability to reactivate. Our study is the first to show that HHV-6B specifically induces hypomethylated regions close to the telomeres and that integrating viruses may use the host methylation machinery to facilitate their integration process. The results from this study contribute to knowledge of HHV-6B biology and virus-host interaction. This in turn will lead to further progress in our understanding of the underlying mechanisms by which HHV-6B contributes to pathological processes and may have important implications in both disease prevention and treatment.


Assuntos
Cromossomos Humanos Par 17/metabolismo , Metilação de DNA , Expressão Gênica , Herpesvirus Humano 6/genética , Herpesvirus Humano 6/fisiologia , Integração Viral , Citosina/química , DNA Viral/genética , Proteínas de Ligação a DNA/genética , Genoma Viral , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas/genética , Telômero , Ativação Viral/genética , Latência Viral/genética
13.
PLoS One ; 12(2): e0170395, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28170401

RESUMO

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNß) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNß preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNß-1a subcutaneous (s.c.) and IFNß-1b s.c. in favor of the least immunogenic preparation IFNß-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNß-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNß-1a i.m. (1.41 and 2.27 years), IFNß-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNß-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNß ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.


Assuntos
Anticorpos/imunologia , Fatores Imunológicos/efeitos adversos , Interferon beta/efeitos adversos , Esclerose Múltipla/imunologia , Natalizumab/efeitos adversos , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Europa (Continente) , Feminino , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Lactente , Recém-Nascido , Interferon beta/imunologia , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Natalizumab/imunologia , Natalizumab/uso terapêutico , Estudos Retrospectivos , Fatores Sexuais , Fatores de Tempo , Adulto Jovem
14.
J Interferon Cytokine Res ; 36(12): 667-670, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27918711

RESUMO

Previous epidemiologic studies showed an increased risk of neutralizing antibody (NAb) development against Interferon beta in multiple sclerosis patients who smoke. Cotinine is an easily detectable metabolite of nicotine and, therefore, can be used as an objective surrogate marker for smoking status. We measured cotinine levels in NAb-positive and NAb-negative patients to find a potential association of nicotine consumption and NAb development. Cotinine was measured in 37 patients with known smoking status and in 123 patients with unknown smoking status, all of whom were routinely tested for NAb. Cotinine was detected by an enzyme-linked immunosorbent assay, inhibition assay. We compared cotinine levels by NAb status and tested for the strength of association between cotinine and NAb status. We found a discrepancy between smoking status stated by patients and status defined by cotinine levels in 7 of 37 patients. In both cohorts, together with and without previously known smoking status (n = 160), we found 34% and 39% smokers, respectively, as defined by cotinine levels in NAb-negative and NAb-positive patients (P = 0.511). In our analysis, smoking was not associated with higher risk of NAb development. Moreover, smoking habits stated by patients do not always correlate with cotinine levels.


Assuntos
Anticorpos Neutralizantes/imunologia , Autoanticorpos/imunologia , Cotinina/sangue , Interferon beta/imunologia , Esclerose Múltipla/sangue , Esclerose Múltipla/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Áustria , Autoanticorpos/sangue , Biomarcadores , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Prognóstico , Fumar , Adulto Jovem
15.
PLoS One ; 11(11): e0162752, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27806057

RESUMO

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNß)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNß-1a subcutaneous and IFNß-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNß-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFNß therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNß in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNß. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.


Assuntos
Anticorpos Anti-Idiotípicos/imunologia , Anticorpos/imunologia , Interferon beta/efeitos adversos , Interferon beta/imunologia , Esclerose Múltipla/complicações , Natalizumab/efeitos adversos , Natalizumab/imunologia , Adulto , Idoso , Anticorpos/sangue , Anticorpos Anti-Idiotípicos/sangue , Estudos de Coortes , Bases de Dados Factuais , Europa (Continente)/epidemiologia , Feminino , Humanos , Interferon beta/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/mortalidade , Natalizumab/uso terapêutico , Avaliação de Resultados da Assistência ao Paciente , Vigilância da População , Modelos de Riscos Proporcionais , Fatores de Risco
16.
J Immunol Methods ; 430: 1-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26779831

RESUMO

Neutralizing anti-drug antibodies (NAbs) against therapeutic interferon beta (IFNß) in people with multiple sclerosis (MS) are measured with cell-based bioassays. The aim of this study was to redevelop and validate two luciferase reporter-gene bioassays, LUC and iLite, using a cut-point approach to identify NAb positive samples. Such an approach is favored by the pharmaceutical industry and governmental regulatory agencies as it has a clear statistical basis and overcomes the limitations of the current assays based on the Kawade principle. The work was conducted following the latest assay guidelines. The assays were re-developed and validated as part of the "Anti-Biopharmaceutical Immunization: Prediction and analysis of clinical relevance to minimize the risk" (ABIRISK) consortium and involved a joint collaboration between four academic laboratories and two pharmaceutical companies. The LUC assay was validated at Innsbruck Medical University (LUCIMU) and at Rigshospitalet (LUCRH) Copenhagen, and the iLite assay at Karolinska Institutet, Stockholm. For both assays, the optimal serum sample concentration in relation to sensitivity and recovery was 2.5% (v/v) in assay media. A Shapiro-Wilk test indicated a normal distribution for the majority of runs, allowing a parametric approach for cut-point calculation to be used, where NAb positive samples could be identified with 95% confidence. An analysis of means and variances indicated that a floating cut-point should be used for all assays. The assays demonstrated acceptable sensitivity for being cell-based assays, with a confirmed limit of detection in neat serum of 1519 ng/mL for LUCIMU, 814 ng/mL for LUCRH, and 320 ng/mL for iLite. Use of the validated cut-point assay, in comparison with the previously used Kawade method, identified 14% more NAb positive samples. In conclusion, implementation of the cut-point design resulted in increased sensitivity to detect NAbs. However, the clinical significance of these low positive titers needs to be further evaluated.


Assuntos
Anticorpos Neutralizantes/sangue , Genes Reporter , Interferon beta/imunologia , Bioensaio , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Humanos , Luciferases , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Testes de Neutralização , Sensibilidade e Especificidade
17.
J Virol Methods ; 227: 47-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26542463

RESUMO

When using relative gene expression for quantification of RNA it is crucial that the reference genes used for normalization do not change with the experimental condition. We aimed at investigating the expressional stability of commonly used reference genes during Human herpesvirus 6B (HHV-6B) infection. Expression of eight commonly used reference genes were investigated with quantitative PCR in a T-cell line infected with HHV-6B. The stability of genes was investigated using the 2(-ΔΔCT) method and the algorithms BestKeeper, GeNorm and NormFinder. Our results indicate that peptidylprolyl isomerase A (PPIA) is the most stably expressed gene while TATA box binding protein (TBP) is the least stably expressed gene during HHV-6B infection. In a confirmatory experiment, TBP was demonstrated to be dose and time dependently upregulated by HHV-6B. The stability of PPIA is in line with other studies investigating different herpesvirus infections whereas the finding that HHV-6B significantly upregulates TBP is novel and most likely specific to HHV-6B.


Assuntos
Herpesvirus Humano 6/genética , Peptidilprolil Isomerase/genética , Infecções por Roseolovirus/genética , Proteína de Ligação a TATA-Box/genética , Biomarcadores , Expressão Gênica , Humanos , Peptidilprolil Isomerase/metabolismo , Infecções por Roseolovirus/enzimologia , Infecções por Roseolovirus/metabolismo , Proteína de Ligação a TATA-Box/metabolismo , Regulação para Cima
18.
J Immunol ; 195(7): 3262-72, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26283480

RESUMO

NK cells play an important role in the defense against viral infections. However, little is known about the regulation of NK cell responses during the first days of acute viral infections in humans. In this study, we used the live attenuated yellow fever virus (YFV) vaccine 17D as a human in vivo model to study the temporal dynamics and regulation of NK cell responses in an acute viral infection. YFV induced a robust NK cell response in vivo, with an early activation and peak in NK cell function at day 6, followed by a delayed peak in Ki67 expression, which was indicative of proliferation, at day 10. The in vivo NK cell response correlated positively with plasma type I/III IFN levels at day 6, as well as with the viral load. YFV induced an increased functional responsiveness to IL-12 and IL-18, as well as to K562 cells, indicating that the NK cells were primed in vivo. The NK cell responses were associated primarily with the stage of differentiation, because the magnitude of induced Ki67 and CD69 expression was distinctly higher in CD57(-) NK cells. In contrast, NK cells expressing self- and nonself-HLA class I-binding inhibitory killer cell Ig-like receptors contributed, to a similar degree, to the response. Taken together, our results indicate that NK cells are primed by type I/III IFN in vivo early after YFV infection and that their response is governed primarily by the differentiation stage, independently of killer cell Ig-like receptor/HLA class I-mediated inhibition or education.


Assuntos
Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Adulto , Anticorpos Neutralizantes/imunologia , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos T/biossíntese , Linfócitos B/imunologia , Antígenos CD57/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Interferon Tipo I/sangue , Subunidade p35 da Interleucina-12/imunologia , Interleucina-18/imunologia , Células K562 , Antígeno Ki-67/biossíntese , Células Matadoras Naturais/citologia , Lectinas Tipo C/biossíntese , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Linfócitos T/imunologia , Vacinas Atenuadas/imunologia , Carga Viral/imunologia , Vacinas Virais/imunologia
19.
Front Microbiol ; 6: 388, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25983728

RESUMO

Human herpesvirus 6A and 6B are ß-herpesviruses approaching 100% seroprevalance worldwide. These viruses are involved in several clinical syndromes and have important immunomodulatory effects. Dendritic cells (DC) are key players in innate and adaptive immunity. Accordingly, DC are implicated in the pathogenesis of many human diseases, including infections. In this review the effects of HHV-6 infection on DC will be discussed.

20.
Expert Rev Clin Immunol ; 10(6): 697-9, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24780058

RESUMO

The advent of biopharmaceuticals (BPs) has led to significant improvements in the treatment of many chronic inflammatory diseases, and the number of BPs on the market and of diseases treated reflects their success. However, repetitive parenteral administration and intrinsic immunogenic properties of the drug can elicit an immune response, leading to production of anti-drug antibodies (ADA). This is a major limitation of the use of BPs and has to be taken into consideration in clinical practice and during drug development. With increasing knowledge about the immunogenicity of BPs and regular ADA testing in patients, we ensure optimized long-term treatment for the individual and thus optimal use of health care resources. This field has already been extensively investigated in the treatment of multiple sclerosis with IFN-ß, but there is a clear need for consensus from academia, health care providers and the BP industry in managing ADA across all BPs and diseases.


Assuntos
Anticorpos , Fatores Imunológicos , Esclerose Múltipla , Anticorpos/imunologia , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Interferon beta/imunologia , Interferon beta/uso terapêutico , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Retratos como Assunto
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA