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1.
Liver Int ; 44(9): 2293-2302, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38780109

RESUMO

BACKGROUND & AIMS: Total serum bile acid (TSBA) levels are elevated in patients with primary biliary cholangitis (PBC) and may mediate cholestatic pruritus. Linerixibat, an ileal bile acid transporter inhibitor, improved pruritus in patients with PBC. We explored the relationship between linerixibat dose, TSBA concentration, and pruritus. METHODS: Data from Phase 1/2 trials were used to develop a population kinetic-pharmacodynamic model to characterize the linerixibat dose-TSBA relationship. Individual Bayesian parameter estimates for participants in the GLIMMER study were used to derive the area under the TSBA concentration curve over 24 h (AUC0-24). Time-matched post hoc estimates of AUC0-24 were correlated with pruritus reported on a 0-10 numerical rating scale. Baseline TSBA concentration was correlated with change from baseline (ΔBL) in monthly itch score (MIS). ΔBL in model-estimated TSBA AUC0-24 was correlated with time-matched ΔBL in weekly itch score (WIS) or MIS. RESULTS: Linerixibat dose dependently reduced TSBA AUC0-24, reaching steady state after 5 days. Baseline TSBA levels in GLIMMER did not correlate with ΔBL in MIS. ΔBL in TSBA AUC0-24 correlated with improved WIS over 12 weeks of treatment (r = 0.52, p < 0.0001). Of participants with a ≥30% decrease in TSBA AUC0-24, 60% were pruritus responders (≥2-point improvement in WIS from baseline). CONCLUSIONS: Linerixibat treatment leads to rapid, dose-dependent TSBA reductions. Baseline TSBA levels do not correlate with on-treatment pruritus change, suggesting they do not predict linerixibat response. Change in TSBA AUC0-24 correlates significantly with, and can be predictive of, pruritus improvement in patients with PBC.


Assuntos
Ácidos e Sais Biliares , Cirrose Hepática Biliar , Prurido , Humanos , Prurido/tratamento farmacológico , Prurido/etiologia , Prurido/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/tratamento farmacológico , Ácidos e Sais Biliares/sangue , Teorema de Bayes , Idoso , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Adulto , Resultado do Tratamento , Metilaminas , Tiazepinas
2.
Inorg Chem ; 63(16): 7161-7176, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38591969

RESUMO

A quantitative, rapid, endothermic dissolution of U3O8 in C4mim·PF6 (1-alkyl-3-methyl imidazolium hexafluorophosphate) has been achieved within 2 h at 65 °C by in situ generated fluoride ions by pre-equilibrating the ionic liquid with suitable concentrations of nitric acid. The efficiency of the dissolution followed the trend: UO3 > UO2 > U3O8. The fluoride generation was found to increase with the concentration of nitric acid being equilibrated, the water content of the ionic liquid, and also the time of equilibration. The rate of dissolution of U3O8 followed the trend: C4mim·PF6> C6mim·PF6 > C8mim·PF6. The maximum loading observed for the present case was 200 mg mL-1 which is considered to be quite high with an ionic liquid. The effects of different acid pre-equilibration (HClO4, HCl) on F- generation and subsequent dissolution characteristics have also been investigated. The in situ F- generation, as well as U3O8 dissolution, were found to predominantly follow a pseudo-second-order rate kinetics, while the rate constants for U3O8 dissolution were found to be higher than that of F- generation. The dissolved uranium was successfully electrodeposited on a Cu plate, as confirmed by EDXRF, while the formation of UO2 was revealed from the XRD pattern of the deposit.

3.
Eur Respir J ; 61(2)2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36229048

RESUMO

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19. METHODS: In this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18-79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28. RESULTS: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI -0.8-11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2-33.1%, p=0.009) was observed in the predefined 70-79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI -9.3-11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19. CONCLUSIONS: There was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.


Assuntos
COVID-19 , Insuficiência Respiratória , Adulto , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Anticorpos Monoclonais Humanizados , Método Duplo-Cego , Resultado do Tratamento
4.
Ann Rheum Dis ; 82(12): 1527-1537, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37696589

RESUMO

OBJECTIVES: To investigate the efficacy and safety of otilimab, an anti-granulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis and an inadequate response to conventional synthetic (cs) and biologic disease-modifying antirheumatic drugs (DMARDs) and/or Janus kinase inhibitors. METHODS: ContRAst 3 was a 24-week, phase III, multicentre, randomised controlled trial. Patients received subcutaneous otilimab (90/150 mg once weekly), subcutaneous sarilumab (200 mg every 2 weeks) or placebo for 12 weeks, in addition to csDMARDs. Patients receiving placebo were switched to active interventions at week 12 and treatment continued to week 24. The primary end point was the proportion of patients achieving an American College of Rheumatology ≥20% response (ACR20) at week 12. RESULTS: Overall, 549 patients received treatment. At week 12, there was no significant difference in the proportion of ACR20 responders with otilimab 90 mg and 150 mg versus placebo (45% (p=0.2868) and 51% (p=0.0596) vs 38%, respectively). There were no significant differences in Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, pain Visual Analogue Scale or Functional Assessment of Chronic Illness Therapy-Fatigue scores with otilimab versus placebo at week 12. Sarilumab demonstrated superiority to otilimab in ACR20 response and secondary end points. The incidence of adverse or serious adverse events was similar across treatment groups. CONCLUSIONS: Otilimab demonstrated an acceptable safety profile but failed to achieve the primary end point of ACR20 and improve secondary end points versus placebo or demonstrate non-inferiority to sarilumab in this patient population. TRIAL REGISTRATION NUMBER: NCT04134728.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Antirreumáticos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Índice de Gravidade de Doença , Resultado do Tratamento , Método Duplo-Cego , Metotrexato/uso terapêutico
5.
Ann Rheum Dis ; 82(12): 1516-1526, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37699654

RESUMO

OBJECTIVES: To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis. METHODS: Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. PRIMARY ENDPOINT: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12. RESULTS: The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. PRIMARY ENDPOINT: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups. CONCLUSIONS: Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. TRIAL REGISTRATION NUMBERS: NCT03980483, NCT03970837.


Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Humanos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/induzido quimicamente , Metotrexato/uso terapêutico , Produtos Biológicos/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Phys Chem Chem Phys ; 24(18): 10915-10927, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35452069

RESUMO

A novel approach to generate a wide range of color characteristics such as near white, yellow, orange and red in MgF2, by proper tailoring of the defect structure and varying the composition of Eu3+ and Tb3+ dopant ions have been presented here. It has been observed from positron annihilation lifetime spectroscopy (PALS) study that various defect centers such as mono vacancies and their cluster forms exist in the system, whose amount varies upon varying the dopant ion's composition. The experimentally observed positron lifetime values of the defect centers also matched well with the theoretically calculated lifetime values using the MIKA-DOPPLER package. It has been found that a few vacancies or defect centers act as color centers, while the cluster vacancies change the local symmetry of the rare earth ion by inducing more distortion surrounding them thereby resulting in different emission characteristics in the photoluminescence (PL) study. The defect-related host emission in combination with the green and red emission from Tb3+ and Eu3+ ions generated near-white-light in some of the compounds, while other compounds showed a variety of other color characteristics due to the Tb3+ → Eu3+energy transfer dynamics. The various defect-related emissions, the role of the defect-related trap state in the decay kinetics and the energy-transfer dynamics were also understood by analyzing the electronic structure using HSE06 hybrid functional calculation.

7.
Ann Rheum Dis ; 80(3): 339-348, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33168545

RESUMO

OBJECTIVES: To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial. METHODS: Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored. RESULTS: Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified. CONCLUSIONS: Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.


Assuntos
Síndrome de Sjogren , Abatacepte/uso terapêutico , Humanos , Medidas de Resultados Relatados pelo Paciente , Índice de Gravidade de Doença , Síndrome de Sjogren/complicações , Síndrome de Sjogren/tratamento farmacológico , Resultado do Tratamento
8.
PLoS Comput Biol ; 14(3): e1006069, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29561846

RESUMO

Genetic differences contribute to variations in the immune response mounted by different individuals to a pathogen. Such differential response can influence the spread of infectious disease, indicating why such diseases impact some populations more than others. Here, we study the impact of population-level genetic heterogeneity on the epidemic spread of different strains of H1N1 influenza. For a population with known HLA class-I allele frequency and for a given H1N1 viral strain, we classify individuals into sub-populations according to their level of susceptibility to infection. Our core hypothesis is that the susceptibility of a given individual to a disease such as H1N1 influenza is inversely proportional to the number of high affinity viral epitopes the individual can present. This number can be extracted from the HLA genetic profile of the individual. We use ethnicity-specific HLA class-I allele frequency data, together with genome sequences of various H1N1 viral strains, to obtain susceptibility sub-populations for 61 ethnicities and 81 viral strains isolated in 2009, as well as 85 strains isolated in other years. We incorporate these data into a multi-compartment SIR model to analyse the epidemic dynamics for these (ethnicity, viral strain) epidemic pairs. Our results show that HLA allele profiles which lead to a large spread in individual susceptibility values can act as a protective barrier against the spread of influenza. We predict that populations skewed such that a small number of highly susceptible individuals coexist with a large number of less susceptible ones, should exhibit smaller outbreaks than populations with the same average susceptibility but distributed more uniformly across individuals. Our model tracks some well-known qualitative trends of influenza spread worldwide, suggesting that HLA genetic diversity plays a crucial role in determining the spreading potential of different influenza viral strains across populations.


Assuntos
Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/epidemiologia , Simulação por Computador , Surtos de Doenças , Suscetibilidade a Doenças/epidemiologia , Epidemias , Epitopos , Etnicidade/genética , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia
9.
Bioinformatics ; 32(15): 2297-305, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27153594

RESUMO

MOTIVATION: T-cell epitopes serve as molecular keys to initiate adaptive immune responses. Identification of T-cell epitopes is also a key step in rational vaccine design. Most available methods are driven by informatics and are critically dependent on experimentally obtained training data. Analysis of a training set from Immune Epitope Database (IEDB) for several alleles indicates that the sampling of the peptide space is extremely sparse covering a tiny fraction of the possible nonamer space, and also heavily skewed, thus restricting the range of epitope prediction. RESULTS: We present a new epitope prediction method that has four distinct computational modules: (i) structural modelling, estimating statistical pair-potentials and constraint derivation, (ii) implicit modelling and interaction profiling, (iii) feature representation and binding affinity prediction and (iv) use of graphical models to extract peptide sequence signatures to predict epitopes for HLA class I alleles. CONCLUSIONS: HLaffy is a novel and efficient epitope prediction method that predicts epitopes for any Class-1 HLA allele, by estimating the binding strengths of peptide-HLA complexes which is achieved through learning pair-potentials important for peptide binding. It relies on the strength of the mechanistic understanding of peptide-HLA recognition and provides an estimate of the total ligand space for each allele. The performance of HLaffy is seen to be superior to the currently available methods. AVAILABILITY AND IMPLEMENTATION: The method is made accessible through a webserver http://proline.biochem.iisc.ernet.in/HLaffy CONTACT: : nchandra@biochem.iisc.ernet.in SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional , Epitopos de Linfócito T , Peptídeos , Algoritmos , Alelos , Sequência de Aminoácidos , Humanos
10.
PLoS Pathog ; 11(6): e1004978, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26083387

RESUMO

Respiratory syncytial virus (RSV) infection can result in severe disease partially due to its ability to interfere with the initiation of Th1 responses targeting the production of type I interferons (IFN) and promoting a Th2 immune environment. Epigenetic modulation of gene transcription has been shown to be important in regulating inflammatory pathways. RSV-infected bone marrow-derived DCs (BMDCs) upregulated expression of Kdm5b/Jarid1b H3K4 demethylase. Kdm5b-specific siRNA inhibition in BMDC led to a 10-fold increase in IFN-ß as well as increases in IL-6 and TNF-α compared to control-transfected cells. The generation of Kdm5bfl/fl-CD11c-Cre+ mice recapitulated the latter results during in vitro DC activation showing innate cytokine modulation. In vivo, infection of Kdm5bfl/fl-CD11c-Cre+ mice with RSV resulted in higher production of IFN-γ and reduced IL-4 and IL-5 compared to littermate controls, with significantly decreased inflammation, IL-13, and mucus production in the lungs. Sensitization with RSV-infected DCs into the airways of naïve mice led to an exacerbated response when mice were challenged with live RSV infection. When Kdm5b was blocked in DCs with siRNA or DCs from Kdm5bfl/fl-CD11c-CRE mice were used, the exacerbated response was abrogated. Importantly, human monocyte-derived DCs treated with a chemical inhibitor for KDM5B resulted in increased innate cytokine levels as well as elicited decreased Th2 cytokines when co-cultured with RSV reactivated CD4+ T cells. These results suggest that KDM5B acts to repress type I IFN and other innate cytokines to promote an altered immune response following RSV infection that contributes to development of chronic disease.


Assuntos
Citocinas/biossíntese , Proteínas de Ligação a DNA/imunologia , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Histona Desmetilases com o Domínio Jumonji/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Imunoprecipitação da Cromatina , Técnicas de Cocultura , Citocinas/imunologia , Modelos Animais de Doenças , Imunidade Inata/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Vírus Sinciciais Respiratórios/imunologia , Transfecção
11.
J Immunol ; 192(3): 996-1003, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24367028

RESUMO

Notch activation plays an important role in T cell development and mature T cell differentiation. In this study, we investigated the role of Notch activation in a mouse model of respiratory syncytial virus (RSV)-exacerbated allergic airway disease. During RSV exacerbation, in vivo neutralization of a specific Notch ligand, Delta-like ligand (Dll)-4, significantly decreased airway hyperreactivity, mucus production, and Th2 cytokines. Lunatic Fringe (Lfng), a glycosyltransferase that enhances Notch activation by Dll4, was increased during RSV exacerbation. Lfng loss of function in Th2-skewed cells inhibited Dll4-Notch activation and subsequent IL-4 production. Further knockdown of Lfng in T cells in CD4Cre(+)Lfng(fl/fl) mice showed reduced Th2 response and disease pathology during RSV exacerbation. Finally, we identified STAT5-binding cis-acting regulatory element activation as a critical driver of Lfng transcriptional activation. These data demonstrate that STAT5-dependent amplification of Notch-modifying Lfng augments Th2 response via Dll4 and is critical for amplifying viral exacerbation during allergic airway disease.


Assuntos
Citocinas/biossíntese , Glicosiltransferases/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Membrana/fisiologia , Hipersensibilidade Respiratória/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Fator de Transcrição STAT5/fisiologia , Células Th2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação ao Cálcio , Células Cultivadas , Imunoprecipitação da Cromatina , Baratas , Citocinas/genética , Modelos Animais de Doenças , Glicosiltransferases/antagonistas & inibidores , Glicosiltransferases/biossíntese , Glicosiltransferases/genética , Proteínas de Insetos/imunologia , Proteínas de Insetos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores Notch/fisiologia , Hipersensibilidade Respiratória/complicações , Infecções por Vírus Respiratório Sincicial/complicações , Fator de Transcrição STAT5/antagonistas & inibidores , Fator de Transcrição STAT5/imunologia , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos , Células Th2/imunologia
12.
Immunol Cell Biol ; 93(6): 522-32, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25708537

RESUMO

T-cell responses in humans are initiated by the binding of a peptide antigen to a human leukocyte antigen (HLA) molecule. The peptide-HLA complex then recruits an appropriate T cell, leading to cell-mediated immunity. More than 2000 HLA class-I alleles are known in humans, and they vary only in their peptide-binding grooves. The polymorphism they exhibit enables them to bind a wide range of peptide antigens from diverse sources. HLA molecules and peptides present a complex molecular recognition pattern, as many peptides bind to a given allele and a given peptide can be recognized by many alleles. A powerful grouping scheme that not only provides an insightful classification, but is also capable of dissecting the physicochemical basis of recognition specificity is necessary to address this complexity. We present a hierarchical classification of 2010 class-I alleles by using a systematic divisive clustering method. All-pair distances of alleles were obtained by comparing binding pockets in the structural models. By varying the similarity thresholds, a multilevel classification was obtained, with 7 supergroups, each further subclassifying to yield 72 groups. An independent clustering performed based only on similarities in their epitope pools correlated highly with pocket-based clustering. Physicochemical feature combinations that best explain the basis of clustering are identified. Mutual information calculated for the set of peptide ligands enables identification of binding site residues contributing to peptide specificity. The grouping of HLA molecules achieved here will be useful for rational vaccine design, understanding disease susceptibilities and predicting risk of organ transplants.


Assuntos
Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Alelos , Sequência de Aminoácidos , Sítios de Ligação , Análise por Conglomerados , Reações Cruzadas/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/classificação , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade Celular , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Matrizes de Pontuação de Posição Específica , Ligação Proteica , Conformação Proteica , Reprodutibilidade dos Testes
13.
Am J Pathol ; 184(6): 1807-18, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24726498

RESUMO

IL-27 is a heterodimeric cytokine composed of the subunits p28 and Epstein-Barr virus induced gene (EBI)-3 and is known for its effects on T-cell function and differentiation. IL-27 signals through the widely expressed IL-27 receptor (IL-27R), composed of the ligand-specific IL-27Rα chain and gp130. Engagement of the IL-27R activates STAT1 signaling, induces the expression of the type 1 helper T-cell (Th1) cytokine, interferon γ, and suppresses the differentiation of Th2 and Th17 cells. This study investigates the role of IL-27 signaling in respiratory syncytial virus (RSV) infection using IL-27Rα-deficient mice (IL-27rKO). Analysis of lungs from RSV-infected IL-27rKO mice showed exacerbation of mucus secretion compared with wild type, as well as enhanced expression of Muc5ac and Gob5 mRNA, markers of goblet cell metaplasia/hyperplasia. When compared with wild-type mice, RSV-challenged IL-27rKO mice had enhanced expression of Th17-associated cytokine IL-17a and an imbalance between Th1 and Th2 cytokine levels. Neutralization of IL-17 in RSV-infected IL-27rKO mice resulted in a significant decrease in the pulmonary mucus response and inhibition of the Th2-associated cytokines. Interestingly, IL-17 blockage led to an increase in the expression of IL-27 subunits p28 and EBI-3 in the lungs and lymph nodes of RSV-infected mice. Thus, IL-27 functions as a regulatory cytokine during RSV pathogenesis by suppressing the development of Th17 cells, but it also appears to be regulated by IL-17 induced by the virus.


Assuntos
Interleucina-17/imunologia , Receptores de Citocinas/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sinciciais Respiratórios/imunologia , Células Th17/imunologia , Células Th2/imunologia , Animais , Canais de Cloreto/genética , Canais de Cloreto/imunologia , Interleucina-17/genética , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor , Mucina-5AC/genética , Mucina-5AC/imunologia , Mucoproteínas/genética , Mucoproteínas/imunologia , Muco/imunologia , Receptores de Citocinas/genética , Receptores de Interleucina , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Células Th17/patologia , Células Th2/patologia
14.
J Immunol ; 191(5): 2526-37, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23894198

RESUMO

Recent work demonstrated the importance of macroautophagy in dendritic cell (DC) maturation and innate cytokine production upon viral infection through delivery of cytoplasmic viral components to intracellular TLRs. To study the functional consequences of impaired autophagosome formation during a respiratory syncytial virus (RSV) infection, mice harboring significant autophagy defects due to Beclin-1 haploinsufficiency (Beclin-1(+/-)) were used. Upon RSV infection in vivo, lungs of Beclin-1(+/-) mice showed increased Th2 cytokine production, mucus secretion, and lung infiltration of eosinophils and inflammatory DCs. Although isolated airway epithelial cells from Beclin-1(+/-) mice demonstrated little change compared with wild-type mice, Beclin-1(+/-) pulmonary and bone marrow-derived DCs showed decreased expression of MHC class II and innate cytokine production upon RSV infection. Further examination indicated that Beclin-1(+/-) DCs stimulated less IFN-γ and IL-17 production by cocultured CD4(+) T cells and increased Th2 cytokine production in comparison with wild-type controls. Finally, adoptive transfer of RSV-infected Beclin-1(+/-) DCs into the airways of wild-type mice produced severe lung pathology and increased Th2 cytokine production upon subsequent RSV challenge compared with wild-type DC transfer controls. These results indicate a critical role for autophagy in DCs during pulmonary viral infection, facilitating appropriate antiviral adaptive immune responses.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Autofagia/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Infecções por Vírus Respiratório Sincicial/metabolismo , Infecções por Vírus Respiratório Sincicial/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
15.
Curr Top Microbiol Immunol ; 372: 139-54, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24362688

RESUMO

The innate immune response has a critical role in the initial stages of respiratory syncytial virus (RSV) infection and provides important instructional control that determines the direction of the acquired immune response and the severity of subsequent disease. Contributions to innate immunity include responses initiated in epithelial cells, dendritic cells, and macrophages. The initiation and the intensity of the response depends upon the recognition of pathogen-associated molecular patterns (PAMPs) that activate various pattern recognition receptors (PRRs) such as toll-like receptors (TLR), RIG-I-like receptors (RLR), and NOD-like receptors (NLR), that induce innate cytokines and chemokines that promote inflammation and direct the recruitment of immune cells as well as promote anti-viral responses. In this review, we summarize the results of numerous studies that have characterized the innate immune responses that contribute to the RSV-induced responses and may be important considerations for the development of efficacious vaccine strategies.


Assuntos
Regulação da Expressão Gênica/imunologia , Imunidade Inata , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Imunidade Adaptativa , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Células Epiteliais/imunologia , Células Epiteliais/virologia , Humanos , Macrófagos/imunologia , Macrófagos/virologia , Receptores Notch/genética , Receptores Notch/imunologia , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/patogenicidade , Proteínas Virais de Fusão/imunologia
16.
J Immunol ; 189(12): 5942-53, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23136205

RESUMO

The cytosolic RNA helicases melanoma differentiation-associated gene 5 and retinoic acid-inducible gene-I and their adaptor IFN-ß promoter stimulator (IPS-1) have been implicated in the recognition of viral RNA and the production of type I IFN. Complementing the endosomal TLR, melanoma differentiation-associated gene 5, and retinoic acid-inducible gene-I provides alternative mechanisms for viral detection in cells with reduced phagocytosis or autophagy. The infection route of respiratory syncytial virus (RSV)-via fusion of virus particles with the cell membrane-points to IPS-1 signaling as the pathway of choice for downstream antiviral responses. In the current study, viral clearance and inflammation resolution were indeed strongly affected by the absence of an initial IPS-1-mediated IFN-ß response. Despite the blunted inflammatory response in IPS-1-deficient alveolar epithelial cells, pulmonary macrophages, and CD11b(+) dendritic cells (DC), the lungs of RSV-infected IPS-1-knockout mice showed augmented recruitment of inflammatory neutrophils, monocytes, and DC. Interestingly, pulmonary CD103(+) DC could functionally compensate for IPS-1 deficiency with the upregulation of certain inflammatory cytokines and chemokines, possibly via TLR3 and TLR7 signaling. The increased inflammation and reduced viral clearance in IPS-1-knockout mice was accompanied by increased T cell activation and IFN-γ production. Experiments with bone marrow chimeras indicated that RSV-induced lung pathology was most severe when IPS-1 expression was lacking in both immune and nonimmune cell populations. Similarly, viral clearance was rescued upon restored IPS-1 signaling in either the nonimmune or the immune compartment. These data support a nonredundant function for IPS-1 in controlling RSV-induced inflammation and viral replication.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/virologia , Camundongos , Camundongos Knockout , Infecções por Vírus Respiratório Sincicial/patologia , Vírus Sincicial Respiratório Humano/imunologia , Transdução de Sinais/genética , Carga Viral/genética , Carga Viral/imunologia
17.
Phys Rev E ; 110(3-1): 034117, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39425323

RESUMO

We conduct Monte Carlo simulations to analyze the percolation transition of a nonsymmetric loop model on a regular three-dimensional lattice. We calculate the critical exponents for the percolation transition of this model. The percolation transition occurs at a temperature that is close to, but not exactly, the thermal critical temperature. Our finite-size study on this model yields a correlation length exponent that agrees with that of the three-dimensional XY model with an error margin of 6%.

18.
Phys Rev E ; 110(3-1): 034116, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39425329

RESUMO

We study order-disorder transitions in three-dimensional multicolored loop models using Monte Carlo simulations. We show that the nature of the transition is intimately related to the nature of the loops. The symmetric loops undergo a first-order phase transition, while the nonsymmetric loops show a second-order transition. The critical exponents for the nonsymmetric loops are calculated. In three dimensions, the regular loop model with no interactions is dual to the XY model. We argue that, due to interactions among the colors, the specific-heat exponent is found to be different from that of the regular loop model. The continuous nature of the transition is altered to a discontinuous one due to the strong intercolor interactions.

19.
Arthritis Res Ther ; 26(1): 125, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38918871

RESUMO

BACKGROUND: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). METHODS: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. RESULTS: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. CONCLUSION: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.


Assuntos
Abatacepte , Antirreumáticos , Artrite Juvenil , Biomarcadores , Humanos , Abatacepte/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/sangue , Masculino , Feminino , Criança , Biomarcadores/sangue , Antirreumáticos/uso terapêutico , Calgranulina B/sangue , Adolescente , Resultado do Tratamento , Pré-Escolar , Calgranulina A/sangue , Proteína S100A12/sangue , Proteínas S100/sangue
20.
Bioengineering (Basel) ; 10(6)2023 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-37370605

RESUMO

Porous structured metallic implants are preferable as bone graft substitutes due to their faster tissue integration mediated by bone in-growth and vascularization. The porous scaffolds/implants should also mimic the graded structure of natural bone to ensure a match of mechanical properties. This article presents a method for designing a graded porous structured acetabular implant and identifies suitable parameters for manufacturing the model through additive manufacturing. The design method is based on slice-wise modification to ensure continuity of gradation. Modification of the slices was achieved through the binary image processing route. A geodesic dome-type design was adopted for developing the acetabular cup model from the graded porous structure. The model had a solid shell with the target porosity and pore size gradually changing from 65% and 950 µm, respectively, in the inner side to 75% and 650 µm, respectively, towards the periphery. The required dimensions of the unit structures and the combinations of pore structure and strut diameter necessary to obtain the target porosity and pore size were determined analytically. Suitable process parameters were identified to manufacture the model by Direct Metal Laser Sintering (DMLS) using Ti6Al4V powder after carrying out a detailed experimental study to minimize the variation of surface roughness and warping over different build angles of the strut structures. Dual-contour scanning was implemented to simplify the scan strategy. The minimum diameter of struts that could be manufactured using the selected scanning strategy and scanning parameters was found to be 375 µm. Finally, the model was built and from the micro-CT data, the porosities and pore sizes were found to be closely conforming to the designed values. The stiffness of the structures, as found from compression testing, was also found to match with that of human trabecular bone well. Further, the structure exhibited compliant bending-dominated behaviour under compressive loading.

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