Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Front Immunol ; 9: 2865, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30568660

RESUMO

An important goal for personalized treatment is predicting response to a particular therapeutic. A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome. Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α. By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA- patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/ß-expressing memory B cells in ADA+ vs. ADA- RA patients. We also assessed the predictive value of SIRPα/ß expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRPα/ß-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRPα/ß-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment.


Assuntos
Adalimumab/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Linfócitos B/imunologia , Hipersensibilidade a Drogas/diagnóstico , Adalimumab/administração & dosagem , Adulto , Idoso , Antígenos de Diferenciação/metabolismo , Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Linfócitos B/metabolismo , Biomarcadores/sangue , Estudos Transversais , Hipersensibilidade a Drogas/sangue , Hipersensibilidade a Drogas/imunologia , Feminino , Humanos , Memória Imunológica , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Moléculas de Adesão de Célula Nervosa/metabolismo , Prognóstico , Estudos Prospectivos , Receptores de Superfície Celular/metabolismo , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
2.
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.

3.
Ann Rheum Dis ; 77(10): 1463-1470, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29936438

RESUMO

OBJECTIVES: TNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation. METHODS: We treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs).We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation. RESULTS: In BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy. CONCLUSION: MTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.

4.
J Leukoc Biol ; 97(4): 737-49, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25673294

RESUMO

DCs are the first immune cells to be exposed to allergens, including chemical sensitizers, such as nickel, a human TLR4 agonist that induces DC maturation. In ACD, DCs can interact with PMNs that are recruited and activated, leading, in particular, to ectosome release. The objective of this work was to characterize the effects of PMN-Ect on DC functions in an ACD context. We first developed a standardized protocol to produce, characterize, and quantify ectosomes by use of human PLB-985 cells, differentiated into mature PMN (PLB-Ect). We then studied the in vitro effects of these purified ectosomes on human moDC functions in response to NiSO4 and to LPS, another TLR4 agonist. Confocal fluorescence microscopy showed that PLB-Ect was internalized by moDCs and localized in the lysosomal compartment. We then showed that PLB-Ect down-regulated NiSO4-induced moDC maturation, as witnessed by decreased expression of CD40, CD80, CD83, CD86, PDL-1, and HLA-DR and by decreased levels of IL-1ß, IL-6, TNF-α, and IL-12p40 mRNAs. These effects were related to p38MAPK and NF-κB down-regulation. However, no increase in pan-regulatory DC marker genes (GILZ, CATC, C1QA) was observed; rather, levels of effector DC markers (Mx1, NMES1) were increased. Finally, when these PLB-Ect + NiSO4-treated moDCs were cocultured with CD4(+) T cells, a Th2 cytokine profile seemed to be induced, as shown, in particular, by enhanced IL-13 production. Together, these results suggest that the PMN-Ect can modulate DC maturation in response to nickel, a common chemical sensitizer responsible for ADC.


Assuntos
Alérgenos/imunologia , Antígenos CD/biossíntese , Micropartículas Derivadas de Células/fisiologia , Células Dendríticas/imunologia , Dermatite Alérgica de Contato/imunologia , Regulação da Expressão Gênica/imunologia , Linfocinas/biossíntese , Células Mieloides/imunologia , Neutrófilos/imunologia , Níquel/imunologia , Células Th2/citologia , Alérgenos/farmacologia , Antígenos CD/genética , Antígeno B7-H1/biossíntese , Antígeno B7-H1/genética , Diferenciação Celular , Técnicas de Cocultura , Células Dendríticas/efeitos dos fármacos , Dermatite Alérgica de Contato/etiologia , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/genética , Humanos , Leucemia Mieloide Aguda/patologia , Lipossomos , Linfocinas/genética , Monócitos/citologia , Células Mieloides/ultraestrutura , Neutrófilos/ultraestrutura , Níquel/farmacologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia
5.
Infect Immun ; 80(5): 1891-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22371374

RESUMO

We recently documented the neutrophil response to enterovirulent diffusely adherent Escherichia coli expressing Afa/Dr fimbriae (Afa/Dr DAEC), using the human myeloid cell line PLB-985 differentiated into fully mature neutrophils. Upon activation, particularly during infections, neutrophils release neutrophil extracellular traps (NETs), composed of a nuclear DNA backbone associated with antimicrobial peptides, histones, and proteases, which entrap and kill pathogens. Here, using fluorescence microscopy and field emission scanning electron microscopy, we observed NET production by PLB-985 cells infected with the Afa/Dr wild-type (WT) E. coli strain C1845. We found that these NETs were able to capture, immobilize, and kill WT C1845 bacteria. We also developed a coculture model of human enterocyte-like Caco-2/TC7 cells and PLB-985 cells previously treated with WT C1845 and found, for the first time, that the F-actin cytoskeleton of enterocyte-like cells is damaged in the presence of bacterium-induced NETs and that this deleterious effect is prevented by inhibition of protease release. These findings provide new insights into the neutrophil response to bacterial infection via the production of bactericidal NETs and suggest that NETs may damage the intestinal epithelium, particularly in situations such as inflammatory bowel diseases.


Assuntos
Adesinas de Escherichia coli/metabolismo , Enterócitos/citologia , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Neutrófilos/fisiologia , alfa-Defensinas/metabolismo , Adesinas de Escherichia coli/genética , Linhagem Celular , Técnicas de Cocultura , Escherichia coli/ultraestrutura , Proteínas de Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica/fisiologia , Histonas/metabolismo , Humanos , Peptídeo Hidrolases/metabolismo
6.
Eur Cytokine Netw ; 21(4): 226-31, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21084245

RESUMO

The use of TNF-α antagonists has substantially improved the care of many patients with inflammatory and autoimmune diseases. However, approximately one third of such patients fail to respond well to treatment, regardless of the antagonist used or of the underlying disease. The mechanisms underlying these failures are analyzed in this review, and proposals made concerning how best to adapt therapeutic decisions in these instances.


Assuntos
Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Humanos , Imunidade Humoral , Falha de Tratamento
7.
Infect Immun ; 78(7): 2974-83, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20404079

RESUMO

The enterovirulent Escherichia coli strains potentially involved in inflammatory bowel diseases include diffusely adherent strains expressing Afa/Dr fimbriae (Afa/Dr DAEC). We have previously observed type 1 pilus-mediated interleukin-8 (IL-8) hyperproduction in infected neutrophils. As pathogen induction of host cell death programs and clearance of apoptotic infected cells are crucial for innate immune system homeostasis and host integrity, we examined modulation of neutrophil cell death by Afa/Dr DAEC. Using the human PLB-985 cell line differentiated into fully mature neutrophils, we found that the wild-type enterovirulent E. coli strain C1845 and the recombinant strain DH5alpha/pF1845 (expressing the fimbrial adhesin F1845) similarly induced time-dependent phosphatidylserine (PS) externalization, suggesting a major specific role of this virulence factor. Using small interfering RNA (siRNA) decay-accelerating factor (DAF)-transfected PLB-985 cells, we then showed that this PS externalization was triggered in part by glycosylphosphatidylinositol (GPI)-anchored DAF receptor engagement (leading to tyrosine kinase and protein kinase C activation) and that it required cytoskeleton and lipid raft architectural integrity. PS externalization under these conditions was not dependent on caspases, mitochondria, lysosomes, or reactive oxygen or nitrogen species. F1845-mediated PS externalization was sufficient to enable macrophage engulfment of infected differentiated PLB-985 cells. These findings provide new insights into the neutrophil response to Afa/Dr DAEC infection and highlight a new role for F1845 fimbriae. Interestingly, although apoptosis pathways were not engaged, C1845-infected PLB-985 cells displayed enhanced removal by macrophages, a process that may participate in the resolution of Afa/Dr DAEC infection and related inflammation.


Assuntos
Escherichia coli Enteropatogênica/fisiologia , Proteínas de Escherichia coli/fisiologia , Fímbrias Bacterianas/fisiologia , Fatores de Transcrição/fisiologia , Adesinas de Escherichia coli/fisiologia , Apoptose/fisiologia , Aderência Bacteriana/fisiologia , Western Blotting , Linhagem Celular Tumoral , Infecções por Escherichia coli/microbiologia , Proteínas de Fímbrias/fisiologia , Granulócitos/microbiologia , Granulócitos/fisiologia , Humanos , Lisossomos/microbiologia , Lisossomos/fisiologia , Macrófagos/microbiologia , Macrófagos/fisiologia , Neutrófilos/microbiologia , Neutrófilos/fisiologia , Fagocitose/fisiologia
8.
J Leukoc Biol ; 85(2): 310-21, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19015376

RESUMO

The innate immune response to enteropathogenic bacteria includes chemokine-induced polymorphonuclear neutrophil (PMN) migration across mucosal epithelia leading to bacterial clearance and resolution of infection. Among these bacteria, diffusely adherent Escherichia coli expressing Afa/Dr fimbriae (Afa/Dr DAEC), causing childhood diarrhea, can promote IL-8-dependent PMN transmigration across cultured intestinal epithelial cell monolayers via MAPK pathway activation. However, interactions between PMN and Afa/Dr DAEC are poorly documented and constitute the aim of the present study. Using the human PLB-985 cell line differentiated into fully mature PMN, we described the coordinated response to various E. coli. The rapid and strong release of reactive oxygen species and preformed intragranular mediators (myeloperoxidase and IL-8) is followed by a later TNF-alpha, IL-1beta, and IL-8 synthesis. The use of wild-type (IH11128, C1845, LF82), control (AAEC185), and recombinant (AAEC185 bearing Dr or F1845 fimbriae, AdLF82, or type 1 pili) bacterial strains allowed us to demonstrate that late IL-8 hyperproduction is triggered by type 1 pili but not by Dr or F1845 fimbriae; MAPKs (p38, ERK, Src) and NF-kappaB activations are implicated in this response. Thus, in the course of Afa/Dr DAEC intestinal infection, epithelium- and neutrophil-derived IL-8 could, at least in part, control the flow of neutrophils through the lamina propria. Afa/Dr DAEC-induced IL-8 hyperproduction by PMN might thus be important for inducing and perpetuating local inflammation, and this self-amplifying loop might play a role in the pathogenesis of inflammatory bowel diseases such as Crohn's disease.


Assuntos
Diferenciação Celular , Escherichia coli/imunologia , Fímbrias Bacterianas/imunologia , Interleucina-8/biossíntese , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neutrófilos/enzimologia , Quinases da Família src/metabolismo , Antígenos CD/imunologia , Aderência Bacteriana , Antígeno CD11b/imunologia , Antígenos CD18/imunologia , Moléculas de Adesão Celular/imunologia , Escherichia coli/citologia , Proteínas Ligadas por GPI , Humanos , Lipopolissacarídeos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neutrófilos/citologia , Neutrófilos/microbiologia , Peroxidase/metabolismo , Explosão Respiratória/imunologia , Quinases da Família src/antagonistas & inibidores
9.
Vaccine ; 25(20): 3946-54, 2007 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-17433506

RESUMO

Clostridium difficile pathogenesis is mainly due to toxins A and B. However, the first step of pathogenesis is the colonization process. We evaluated C. difficile surface proteins as vaccine antigens to diminish intestinal colonization in a human flora-associated mouse model. First, we used the flagellar cap protein FliD of C. difficile, in order to test several immunization routes: intranasal, rectal, and intragastric. The rectal route, which is the most efficient, was used to vaccine groups of mice with different antigen combinations. After immunizations, the mice were challenged with the toxigenic C. difficile and a significant statistical difference between the control group and the immunized groups was observed in the colonization levels of C. difficile.


Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/administração & dosagem , Clostridium difficile/crescimento & desenvolvimento , Enterocolite Pseudomembranosa/imunologia , Enterocolite Pseudomembranosa/microbiologia , Intestinos/microbiologia , Administração Retal , Animais , Anticorpos Antibacterianos/biossíntese , Anticorpos Antibacterianos/imunologia , Proteínas da Membrana Bacteriana Externa/química , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Vacinas Bacterianas/imunologia , Toxina da Cólera/imunologia , Toxina da Cólera/farmacologia , Clostridium difficile/imunologia , Cisteína Endopeptidases/química , Cisteína Endopeptidases/imunologia , Feminino , Humanos , Imunidade nas Mucosas/imunologia , Imunoglobulina A/biossíntese , Imunoglobulina A/imunologia , Intestinos/imunologia , Camundongos , Camundongos Endogâmicos C3H
10.
J Med Microbiol ; 54(Pt 2): 193-6, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15673516

RESUMO

Sera from patients with Clostridium difficile-associated disease (CDAD) and sera from a control group were analysed by an ELISA to detect antibodies directed against four surface proteins and toxins A and B of C. difficile. The surface proteins were the flagellar cap protein FliD, the flagellin FliC, the adhesin Cwp66 divided into two domains, Cwp66-Nterminal and Cwp66-Cterminal, and the fibronectin-binding protein Fbp68. For each antigen, antibody levels in the CDAD patient group and in the control group were compared. In the CDAD patient group, the mean of the antibody levels decreased from Cwp66-Cterminal to Fbp68, FliD, toxins B and A, Cwp66-Nterminal and finally FliC, suggesting different immunogenic properties among these adhesins. For Cwp66-Nterminal, FliC, FliD and Fbp68, the antibody level observed in the control group was higher than in the CDAD group with a statistically significant difference whereas the antibody level for toxins A and B was not statistically different. In conclusion, this study suggests that during the clinical course of disease, C. difficile adhesins are able to induce an immune response which could play a role in the defence mechanism of the host.


Assuntos
Anticorpos Antibacterianos/sangue , Infecções por Clostridium/imunologia , Clostridium difficile/imunologia , Glicoproteínas de Membrana/imunologia , Adesinas Bacterianas/análise , Adesinas Bacterianas/imunologia , Adolescente , Adulto , Idoso , Aderência Bacteriana , Criança , Infecções por Clostridium/microbiologia , Clostridium difficile/química , Ensaio de Imunoadsorção Enzimática , Feminino , Flagelina/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA