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1.
Mol Immunol ; 120: 32-42, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045772

RESUMO

The pleiotropic cytokine leukemia inhibitory factor (LIF) is a key gestational factor known to establish dynamic cellular and molecular cross talk at the feto-maternal interface. Previously, we described the regulatory role of the LIF-trophoblast-IL10 axis in the process of macrophage deactivation in response to pro-inflammatory cytokines. However, the direct regulatory effects of LIF in macrophage and trophoblast cell function remains elusive. In this study, we aimed to examine whether and how LIF regulates the behavior of macrophages and trophoblast cells in response to pro-inflammatory stress factors. We found that LIF modulated the activating effects of interferon-gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in macrophages and trophoblast cells by reducing the phosphorylation levels of signal transducer and activator of transcription-1 (Stat1) and -5 (Stat5). Cell activation with IFNγ inhibited cell invasion and migration but this immobilizing effect was abrogated when macrophages and trophoblast cells were deactivated with LIF; macrophage cell motility restitution could in part be explained by the positive effects of LIF in Stat3 activation and matrix metalloproteinase 9 (MMP-9) expression. Pharmacological inhibition of Stat1 and Stat3 indicated that IFNγ-induced Stat1 activation mediated macrophage motility inhibition, and that cell motility in IFNγ-activated macrophages is restored via LIF-induced Stat3 activation and Stat1 inhibition. Moreover, IFNγ-induced TNFα gene expression was also abrogated by LIF through Stat1 inhibition and Stat3 activation. Finally, we have found that cell invasion of trophoblast cells is inhibited when they were cocultured with GM-CSF-differentiated, IFNγ-stimulated macrophages. This effect, however, was inhibited when macrophages were exposed to LIF. Overall, this in vitro study reveals for the first time the anti-inflammatory and pro-gestational activities of LIF by acting directly on macrophages and trophoblast cells.


Assuntos
Mediadores da Inflamação/imunologia , Fator Inibidor de Leucemia/imunologia , Macrófagos/imunologia , Trofoblastos/imunologia , Linhagem Celular , Movimento Celular/imunologia , Técnicas de Cocultura , Feminino , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Ativação de Macrófagos , Macrófagos/citologia , Macrófagos/metabolismo , Troca Materno-Fetal/imunologia , Metaloproteinase 9 da Matriz/metabolismo , Gravidez , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Trofoblastos/citologia , Trofoblastos/metabolismo
2.
Acta Crystallogr F Struct Biol Commun ; 75(Pt 10): 634-639, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584011

RESUMO

An increased level of granulocyte-macrophage colony-stimulating factor has a potential role in the development of autoimmune diseases, and the neutralization of its activity by monoclonal antibodies is a promising therapy for some diseases. Here, the crystal structure of the Fab region of EV1007, a fully human antibody expressed in Chinese hamster ovary cells that was developed from human peripheral blood mononuclear cells, is described. The structure closely resembles that of MB007, which is the Fab region of the same antibody expressed in Escherichia coli [Blech et al. (2012), Biochem. J. 447, 205-215], except at the hinge regions between the immunoglobulin domains and the H3 loop region. This paper presents evidence for the flexibility of the hinge and H3 loop regions of the antibody based on the comparison of two independently solved crystal structures.


Assuntos
Anticorpos Neutralizantes/química , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fragmentos Fab das Imunoglobulinas/química , Animais , Anticorpos Neutralizantes/imunologia , Células CHO , Cricetulus , Cristalografia por Raios X , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Leucócitos Mononucleares , Modelos Moleculares , Conformação Proteica
3.
N Engl J Med ; 381(10): 923-932, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31483963

RESUMO

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 µg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).


Assuntos
Doenças Autoimunes/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Autoanticorpos/sangue , Doenças Autoimunes/diagnóstico por imagem , Método Duplo-Cego , Esquema de Medicação , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/imunologia , Capacidade de Difusão Pulmonar , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Fumar/efeitos adversos , Tomografia Computadorizada por Raios X , Teste de Caminhada
4.
BMJ Case Rep ; 12(9)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31537595

RESUMO

Myelodysplastic syndrome (MDS) is frequently complicated by pulmonary disease. Here, we describe secondary pulmonary alveolar proteinosis (sPAP) that developed during corticosteroid therapy for organising pneumonia (OP) associated with MDS. A 75-year-old woman with MDS complained of cough for 2 weeks. Chest CT showed bilateral patchy consolidations with reversed halo sign. Bronchoalveolar lavage (BAL) examination showed remarkably increased cell density with an increased lymphocyte proportion. Abnormal radiological findings improved rapidly on administration of systemic corticosteroid under the diagnosis of OP; however, they relapsed a few weeks later. Transbronchial lung biopsy showed periodic acid-Schiff stain-positive amorphous materials. Autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF) in serum and BAL fluid (BALF) were both negative, while GM-CSF level in BALF was elevated. The patient was diagnosed with sPAP. When chest radiological findings show exacerbation during corticosteroid therapy for OP in a patient with MDS, physicians should consider sPAP complication as a differential diagnosis.


Assuntos
Corticosteroides/efeitos adversos , Síndromes Mielodisplásicas/complicações , Pneumonia/complicações , Proteinose Alveolar Pulmonar/induzido quimicamente , Corticosteroides/uso terapêutico , Idoso , Grupo com Ancestrais do Continente Asiático , Líquido da Lavagem Broncoalveolar/imunologia , Diagnóstico Diferencial , Evolução Fatal , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Pneumonia/diagnóstico por imagem , Pneumonia/tratamento farmacológico , Proteinose Alveolar Pulmonar/complicações , Insuficiência Respiratória/etiologia , Tomografia Computadorizada por Raios X/métodos
5.
Arthritis Rheumatol ; 71(11): 1943-1954, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31379071

RESUMO

OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is associated with a recently recognized, albeit poorly defined and characterized, lung disease (LD). The objective of this study was to describe the clinical characteristics, risk factors, and histopathologic and immunologic features of this novel inflammatory LD associated with systemic JIA (designated SJIA-LD). METHODS: Clinical data collected since 2010 were abstracted from the medical records of patients with systemic JIA from the Cincinnati Children's Hospital Medical Center. Epidemiologic, cellular, biochemical, genomic, and transcriptional profiling analyses were performed. RESULTS: Eighteen patients with SJIA-LD were identified. Radiographic findings included diffuse ground-glass opacities, subpleural reticulation, interlobular septal thickening, and lymphadenopathy. Pathologic findings included patchy, but extensive, lymphoplasmacytic infiltrates and mixed features of pulmonary alveolar proteinosis (PAP) and endogenous lipoid pneumonia. Compared to systemic JIA patients without LD, those with SJIA-LD were younger at the diagnosis of systemic JIA (odds ratio [OR] 6.5, P = 0.007), more often had prior episodes of macrophage activation syndrome (MAS) (OR 14.5, P < 0.001), had a greater frequency of adverse reactions to biologic therapy (OR 13.6, P < 0.001), and had higher serum levels of interleukin-18 (IL-18) (median 27,612 pg/ml versus 5,413 pg/ml; P = 0.047). Patients with SJIA-LD lacked genetic, serologic, or functional evidence of granulocyte-macrophage colony-stimulating factor pathway dysfunction, a feature that is typical of familial or autoimmune PAP. Moreover, bronchoalveolar lavage (BAL) fluid from patients with SJIA-LD rarely demonstrated proteinaceous material and had less lipid-laden macrophages than that seen in patients with primary PAP (mean 10.5% in patients with SJIA-LD versus 66.1% in patients with primary PAP; P < 0.001). BAL fluid from patients with SJIA-LD contained elevated levels of IL-18 and the interferon-γ-induced chemokines CXCL9 and CXCL10. Transcriptional profiling of the lung tissue from patients with SJIA-LD identified up-regulated type II interferon and T cell activation networks. This signature was also present in SJIA-LD human lung tissue sections that lacked substantial histopathologic findings, suggesting that this activation signature may precede and drive the lung pathology in SJIA-LD. CONCLUSION: Pulmonary disease is increasingly detected in children with systemic JIA, particularly in association with MAS. This entity has distinct clinical and immunologic features and represents an uncharacterized inflammatory LD.


Assuntos
Artrite Juvenil/epidemiologia , Proteinose Alveolar Pulmonar/epidemiologia , Distribuição por Idade , Artrite Juvenil/diagnóstico por imagem , Artrite Juvenil/imunologia , Artrite Juvenil/patologia , Líquido da Lavagem Broncoalveolar , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Criança , Pré-Escolar , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Lactente , Interferon gama/metabolismo , Interleucina-18/imunologia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumopatias/diagnóstico por imagem , Pneumopatias/epidemiologia , Pneumopatias/imunologia , Pneumopatias/patologia , Síndrome de Ativação Macrofágica/epidemiologia , Síndrome de Ativação Macrofágica/imunologia , Masculino , Proteinose Alveolar Pulmonar/diagnóstico por imagem , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/patologia , Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X , Transcriptoma , Regulação para Cima
6.
J Agric Food Chem ; 67(32): 9070-9078, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343168

RESUMO

In this study, an immunologically active novel microparticulate mushroom ß-glucan (PRA-1p) was prepared using an alkali-soluble glucan PRA-1 by an emulsification and cross-linking method. PRA-1 was a hyperbranched (1→3),(1→6)-ß-d-glucan with a degree of branching of 0.89, isolated from the sclerotia of Polyporus rhinocerus. PRA-1 had a rod-like conformation, while PRA-1p exhibited a monodisperse and homogeneous spherical conformation with a diameter ranging from 0.3 to 2.0 µm in water. PRA-1p significantly induced nitric oxide and reactive oxygen species production as well as morphological changes of murine macrophages (RAW 264.7 cells) and upregulated their phagocytic activity. Furthermore, PRA-1p treatment markedly enhanced the secretion of cytokines, including cutaneous T cell-attracting chemokine 27, granulocyte-colony-stimulating factor, monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, macrophage inflammatory protein 2, regulated on activation, normal T cell expressed and secreted, soluble tumor necrosis factor receptor 1, and tissue inhibitors of metalloproteinases. Activation of RAW 264.7 cells triggered by PRA-1p was associated with activation of inducible nitric oxide synthase, nuclear factor κB, extracellular signal-regulated kinase, and protein kinase B. This work suggests that novel PRA-1p derived from the mushroom sclerotia of P. rhinocerus has potential application as an immunostimulatory agent.


Assuntos
Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polyporus/química , beta-Glucanas/química , beta-Glucanas/farmacologia , Animais , Quimiocina CCL27/genética , Quimiocina CCL27/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores Imunológicos/isolamento & purificação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico/imunologia , Fagocitose/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polyporus/imunologia , Células RAW 264.7 , Espécies Reativas de Oxigênio/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , beta-Glucanas/isolamento & purificação
7.
J Immunol ; 203(2): 329-337, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31175163

RESUMO

Despite recent advances in asthma management with anti-IL-5 therapies, many patients have eosinophilic asthma that remains poorly controlled. IL-3 shares a common ß subunit receptor with both IL-5 and GM-CSF but, through α-subunit-specific properties, uniquely influences eosinophil biology and may serve as a potential therapeutic target. We aimed to globally characterize the transcriptomic profiles of GM-CSF, IL-3, and IL-5 stimulation on human circulating eosinophils and identify differences in gene expression using advanced statistical modeling. Human eosinophils were isolated from the peripheral blood of healthy volunteers and stimulated with either GM-CSF, IL-3, or IL-5 for 48 h. RNA was then extracted and bulk sequencing performed. DESeq analysis identified differentially expressed genes and weighted gene coexpression network analysis independently defined modules of genes that are highly coexpressed. GM-CSF, IL-3, and IL-5 commonly upregulated 252 genes and downregulated 553 genes, producing a proinflammatory and survival phenotype that was predominantly mediated through TWEAK signaling. IL-3 stimulation yielded the most numbers of differentially expressed genes that were also highly coexpressed (n = 119). These genes were enriched in pathways involving JAK/STAT signaling. GM-CSF and IL-5 stimulation demonstrated redundancy in eosinophil gene expression. In conclusion, IL-3 produces a distinct eosinophil gene expression program among the ß-chain receptor cytokines. IL-3-upregulated genes may provide a foundation for research into therapeutics for patients with eosinophilic asthma who do not respond to anti-IL-5 therapies.


Assuntos
Citocinas/imunologia , Eosinófilos/imunologia , Expressão Gênica/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interleucina-3/imunologia , Interleucina-5/imunologia , Asma/imunologia , Regulação para Baixo/imunologia , Humanos , Transdução de Sinais/imunologia , Regulação para Cima/imunologia
8.
Nat Commun ; 10(1): 2329, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133636

RESUMO

Variability in bacterial sterilization is a key feature of Mycobacterium tuberculosis (Mtb) disease. In a population of human macrophages, there are macrophages that restrict Mtb growth and those that do not. However, the sources of heterogeneity in macrophage state during Mtb infection are poorly understood. Here, we perform RNAseq on restrictive and permissive macrophages and reveal that the expression of genes involved in GM-CSF signaling discriminates between the two subpopulations. We demonstrate that blocking GM-CSF makes macrophages more permissive of Mtb growth while addition of GM-CSF increases bacterial control. In parallel, we find that the loss of bacterial control that occurs in HIV-Mtb coinfected macrophages correlates with reduced GM-CSF secretion. Treatment of coinfected cells with GM-CSF restores bacterial control. Thus, we leverage the natural variation in macrophage control of Mtb to identify a critical cytokine response for regulating Mtb survival and identify components of the antimicrobial response induced by GM-CSF.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Transdução de Sinais/imunologia , Tuberculose/imunologia , Buffy Coat/citologia , Células Cultivadas , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/microbiologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Macrófagos/microbiologia , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Análise de Sequência de RNA , Tuberculose/microbiologia , Vitamina D/imunologia , Vitamina D/metabolismo
9.
J Immunol ; 202(10): 3033-3040, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988114

RESUMO

Studies have demonstrated the importance of a GM-CSF→IFN regulatory factor 4 (IRF4)→CCL17 pathway, first identified in monocytes/macrophages, for arthritic pain and disease development. In this study, we further investigated the involvement of this new pathway in shaping the inflammatory response using the zymosan-induced peritonitis (ZIP) model. ZIP (8 mg of zymosan, i.p., day 0) was induced in C57BL/6 wild-type (WT), GM-CSF-/- , Irf4-/- , and Ccl17E/E mice. In comparison with WT mice, GM-CSF-/- and Irf4-/- mice had a reduced ZIP response, as judged by a reduced number of neutrophils and macrophages in the peritoneal cavity. Moreover, the phenotype of the ZIP macrophages was altered by a lack of GM-CSF or IRF4 (increased IL-10 secretion and Arg1 mRNA expression), with IRF4 levels being lower in GM-CSF-/- ZIP macrophages than in the WT cells. In addition, GM-CSF ̶IRF4 signaling upregulated MHC class II expression in ZIP macrophages and bone marrow-derived macrophages. Although Ccl17 mRNA expression was reduced in ZIP macrophages in the absence of either GM-CSF or IRF4, thus supporting the presence of the new pathway in inflammatory macrophages, CCL17 did not modulate the inflammatory response, both in terms of number of myeloid cells or the macrophage phenotype. Thus, during an inflammatory response, both macrophage numbers and their phenotype can depend on GM-CSF- and IRF4-dependent signaling independently of CCL17.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fatores Reguladores de Interferon/imunologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Animais , Quimiocina CCL17/genética , Quimiocina CCL17/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Fatores Reguladores de Interferon/genética , Macrófagos/patologia , Camundongos , Camundongos Knockout , Transdução de Sinais/genética , Regulação para Cima/imunologia
10.
Immunity ; 50(4): 796-811, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995500

RESUMO

The ß common chain cytokines GM-CSF, IL-3, and IL-5 regulate varied inflammatory responses that promote the rapid clearance of pathogens but also contribute to pathology in chronic inflammation. Therapeutic interventions manipulating these cytokines are approved for use in some cancers as well as allergic and autoimmune disease, and others show promising early clinical activity. These approaches are based on our understanding of the inflammatory roles of these cytokines; however, GM-CSF also participates in the resolution of inflammation, and IL-3 and IL-5 may also have such properties. Here, we review the functions of the ß common cytokines in health and disease. We discuss preclinical and clinical data, highlighting the potential inherent in targeting these cytokine pathways, the limitations, and the important gaps in understanding of the basic biology of this cytokine family.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Inflamação/imunologia , Interleucina-3/imunologia , Interleucina-5/imunologia , Animais , Doenças Autoimunes/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/deficiência , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hematopoese/imunologia , Humanos , Inflamação/terapia , Interleucina-3/antagonistas & inibidores , Interleucina-3/deficiência , Interleucina-3/genética , Interleucina-5/antagonistas & inibidores , Interleucina-5/deficiência , Interleucina-5/genética , Camundongos , Camundongos Knockout , Família Multigênica , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/imunologia , Receptores de Interleucina-3/genética , Receptores de Interleucina-3/imunologia , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/imunologia , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais , Relação Estrutura-Atividade , Vacinação , Cicatrização/imunologia
11.
Muscle Nerve ; 59(6): 694-698, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30847948

RESUMO

INTRODUCTION: Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. METHODS: To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. RESULTS: Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. DISCUSSION: Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.


Assuntos
Citocinas/imunologia , Imunoglobulina M/imunologia , Paraproteinemias/imunologia , Polineuropatias/imunologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Linfócitos B/imunologia , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-2/imunologia , Interleucina-4/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , Glicoproteína Associada a Mielina/imunologia , Fator de Necrose Tumoral alfa/imunologia
12.
PLoS One ; 14(3): e0213179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30845238

RESUMO

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of pulmonary surfactant in alveolar macrophages and alveoli, resulting in respiratory impairment and an increased risk of opportunistic infections. Autoimmune PAP is an autoimmune lung disease that is caused by autoantibodies directed against granulocyte-macrophage colony-stimulating factor (GM-CSF). A shared feature among many autoimmune diseases is a distinct genetic association to HLA alleles. In the present study, we HLA-typed patients with autoimmune PAP to determine if this disease had any HLA association. We analyzed amino acid and allele associations for HLA-A, B, C, DRB1, DQB1, DPB1, DRB3, DRB4 and DRB5 in 41 autoimmune PAP patients compared to 1000 ethnic-matched controls and did not find any HLA association with autoimmune PAP. Collectively, these data may suggest the absence of a genetic association to the HLA in the development of autoimmune PAP.


Assuntos
Doenças Autoimunes/patologia , Antígenos HLA/genética , Proteinose Alveolar Pulmonar/patologia , Adulto , Alelos , Autoanticorpos/sangue , Doenças Autoimunes/genética , Feminino , Frequência do Gene , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Proteinose Alveolar Pulmonar/genética
13.
J Immunol ; 202(9): 2700-2709, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867240

RESUMO

GM-CSF is required for alveolar macrophage (AM) development shortly after birth and for maintenance of AM functions throughout life, whereas M-CSF is broadly important for macrophage differentiation and self-renewal. However, the comparative actions of GM-CSF and M-CSF on AMs are incompletely understood. Interstitial macrophages (IMs) constitute a second major pulmonary macrophage population. However, unlike AMs, IM responses to CSFs are largely unknown. Proliferation, phenotypic identity, and M1/M2 polarization are important attributes of all macrophage populations, and in this study, we compared their modulation by GM-CSF and M-CSF in murine primary AMs and IMs. CSFs increased the proliferation capacity and upregulated antiapoptotic gene expression in AMs but not IMs. GM-CSF, but not M-CSF, reinforced the cellular identity, as identified by surface markers, of both cell types. GM-CSF, but not M-CSF, increased the expression of both M1 and M2 markers exclusively in AMs. Finally, CSFs enhanced the IFN-γ- and IL-4-induced polarization ability of AMs but not IMs. These first (to our knowledge) data comparing effects on the two pulmonary macrophage populations demonstrate that the activating actions of GM-CSF and M-CSF on primary AMs are not conserved in primary IMs.


Assuntos
Proliferação de Células/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Interferon gama/imunologia , Interleucina-4/imunologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos Alveolares/imunologia , Animais , Antígenos de Diferenciação/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/imunologia , Macrófagos Alveolares/citologia , Masculino , Camundongos
14.
J Biol Chem ; 294(14): 5430-5437, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30804212

RESUMO

Chimeric antigen receptor T-cell (CAR T-cell) therapy has been shown to be clinically effective for managing a variety of hematological cancers. However, CAR T-cell therapy is associated with multiple adverse effects, including neurotoxicity and cytokine release syndrome (CRS). CRS arises from massive cytokine secretion and can be life-threatening, but it is typically managed with an anti-IL-6Ra mAb or glucocorticoid administration. However, these treatments add to a patient's medication burden and address only the CRS symptoms. Therefore, alternative strategies that can prevent CRS and neurotoxicity associated with CAR T-cell treatment are urgently needed. Here, we explored a therapeutic route aimed at preventing CRS rather than limiting its consequences. Using a cytokine-profiling assay, we show that granulocyte-macrophage colony-stimulating factor (GMCSF) is a key CRS-promoting protein. Through a combination of in vitro experiments and gene-editing technology, we further demonstrate that antibody-mediated neutralization or TALEN-mediated genetic inactivation of GMCSF in CAR T-cells drastically decreases available GMCSF and abolishes macrophage-dependent secretion of CRS biomarkers, including monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 6, and IL-8. Of note, we also found that the genetic inactivation of GMCSF does not impair the antitumor function or proliferative capacity of CAR T-cells in vitro We conclude that it is possible to prevent CRS by using "all-in-one" GMCSF-knockout CAR T-cells. This approach may eliminate the need for anti-CRS treatment and may improve the overall safety of CAR T-cell therapies for cancer patients.


Assuntos
Citocinas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Monócitos , Proteínas de Neoplasias/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Citocinas/genética , Edição de Genes , Técnicas de Silenciamento de Genes , Glucocorticoides/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Humanos , Monócitos/imunologia , Monócitos/patologia , Proteínas de Neoplasias/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia
15.
Cancer Sci ; 110(3): 888-902, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30629318

RESUMO

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Neuroblastoma/imunologia , Antígenos CD1/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-12/imunologia , Interleucina-4/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Monócitos/metabolismo
16.
Eur J Clin Microbiol Infect Dis ; 38(4): 617-629, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30680553

RESUMO

Toxoplasma gondii is an intracellular parasite infecting almost all warm-blooded animals. Many studies on vaccination have been performed previously, and micronemal proteins (MICs) have crucial importance in this regard. The current review aims to reveal the efficiency of MICs as target antigen, adjuvants, animal models (species/strain), T. gondii strains for challenge infection, and routes of vaccine to prevent Toxoplasma infection. A comprehensive literature search was performed on April 18, 2018, in several known databases. Studies were included when evaluating vaccines based on MIC against T. gondii compared to that of a control group. Two independent researchers done the search process, study choice, and data extraction. A total of 28 articles published were selected for further analysis. Among them, 57.03% of the studies focused on MIC3 and its epitopes. SAG1 was further used in cocktail vaccines compared to other antigens. GM-CSF and Freund's complete were the predominant adjuvants used. BALB/c mice have been introduced as a proper model for lethal challenge. Virulent T. gondii (RH) was utilized more than other strains for challenge. Among MICs, the results of vaccination with MIC1-4, MIC6, and PLP1 demonstrated significantly strong humoral and cellular immunity, increased survival time, and reduced cyst burden in the mice. This review summarizes the latest results on MIC-based vaccines and presents that the most effective vaccination procedure is the administration of the cocktail vaccines. Our survey can serve as a basis for further studies to develop more efficient novel vaccines against T. gondii for animals and humans.


Assuntos
Antígenos de Protozoários/imunologia , Proteínas de Protozoários/imunologia , Toxoplasma/imunologia , Toxoplasmose/prevenção & controle , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/química , Modelos Animais de Doenças , Adjuvante de Freund/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Camundongos Endogâmicos BALB C , Toxoplasma/patogenicidade , Toxoplasmose/imunologia , Vacinação , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
17.
Int J Rheum Dis ; 22(4): 646-653, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30358109

RESUMO

AIM: The aim of our study was to identify pharmacodynamic biomarkers and assess differential effects of tumor necrosis factor (TNF)- and non-TNF-targeting agents on rheumatoid arthritis (RA) patients with an inadequate response to anti-TNF agents (anti-TNF-IR) in comparison with biologic-naïve patients. METHODS: EARTH EXPLORER 2, a phase IIb trial, evaluated golimumab, an anti-TNF antibody, and mavrilimumab, an granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor antibody, in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Our current study assessed peripheral protein markers and gene expression levels in association with clinical response post-treatment in two disease strata. RESULTS: Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti-TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including interleukin (IL)-6, C-reactive protein, IL2RA, and matrix metalloproteinase 1, in DMARD-IR patients. Golimumab-induced early changes rapidly returned toward baseline concentrations in anti-TNF-IR patients, whereas mavrilimumab-induced changes were maintained through to day 169. RNA sequencing demonstrated gene expression changes at day 169 after administration of mavrilimumab but not golimumab in anti-TNF-IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL-6 change and subsequent clinical responses to golimumab in anti-TNF-IR patients. CONCLUSION: Our results revealed golimumab- and mavrilimumab-specific pharmacodynamic biomarkers, and demonstrated differential biomarker-treatment relationships in anti-TNF-IR and DMARD-IR patients, respectively. Early IL-6 change after anti-TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti-TNF-IR patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores Farmacológicos/sangue , Monitoramento de Medicamentos/métodos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Mediadores da Inflamação/sangue , Proteômica , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Método Duplo-Cego , Feminino , Perfilação da Expressão Gênica , Marcadores Genéticos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologia
18.
Arthritis Rheumatol ; 71(3): 392-402, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30260078

RESUMO

OBJECTIVE: Clinical trials of the anti-interleukin-17A (anti-IL-17A) antibody secukinumab have demonstrated a crucial role of the cytokine IL-17A in the pathogenesis of spondyloarthritis (SpA); however, its cellular source in this condition remains a matter of controversy. Group 3 innate lymphoid cells (ILC3s) have been recently identified as potent producers of proinflammatory cytokines, including IL-17A and IL-22, in a number of different tissues. This study was undertaken to characterize the presence and composition of ILCs, and investigate whether these cells are an important source of IL-17A, in the synovial tissue (ST) of patients with SpA. METHODS: Matched ST, synovial fluid, and peripheral blood (PB) samples were obtained from SpA patients with actively inflamed knee joints. ILC subsets were characterized by flow cytometry. Gene expression analysis at the single-cell level was performed directly ex vivo and after in vitro activation. An IL-17A enzyme-linked immunospot assay was used to detect IL-17A-secreting cells. RESULTS: ILCs, and particularly NKp44+ ILC3s, were expanded in inflamed arthritic joints. Single-cell expression analysis demonstrated that ST ILCs were clearly distinguishable from ST T cells and from their PB counterparts. Expression of the Th17 signature transcripts RORC, AHR, and IL23R was detected in a large proportion of ST ILC3s. These cells were capable of inducing expression of IL22 and CSF2, but not IL17A, in response to in vitro restimulation. CONCLUSION: Our findings demonstrate that absolute and relative numbers of ILC3s are enriched in the synovial joints of patients with SpA. However, these cells are not a significant source of IL-17A in this disease.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Imunidade Inata/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Linfócitos/imunologia , Espondilartrite/imunologia , Adulto , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espondilartrite/patologia , Líquido Sinovial/imunologia
19.
Int J Biol Macromol ; 124: 505-514, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30471397

RESUMO

The aim of the present study was chemical clarification of in vitro Peyer's patch-immunomodulating polysaccharides in sugar cane molasses, and evaluation of in vivo modulating activity on immune function of T lymphocytes in Peyer's patches and on microenvironment of hemopoietic system. Five kinds of glucans, comprising of dextranase-sensitive and activity-related d-glucosyl moieties, were purified as in vitro Peyer's patch-immunomodulating polysaccharides from the molasses. Oral administration of a glucan-enriched subfraction induced IL-2 and GM-CSF-producing T lymphocytes in Peyer's patches, resulting in enhancement of IL-6 production in a hemopoietic microenvironment to boost neutrophil numbers in the peripheral blood stream. Oral administration of purified glucan or glucan-enrich sub-fraction of sugar cane reduced the number of Plasmodium berghei- or P. yoelii-infected erythrocytes in a murine infection model, using polysaccharide alone or via co-administration with the antimalarial drug, artesunate. These results suggested that Peyer's patch-immunomodulating glucans enhanced protective immunity through axis of Peyer's patches-hemopoietic system.


Assuntos
Glucanos/farmacologia , Hematopoese/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Malária/tratamento farmacológico , Nódulos Linfáticos Agregados/efeitos dos fármacos , Saccharum/química , Administração Oral , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Feminino , Expressão Gênica/efeitos dos fármacos , Glucanos/química , Glucanos/isolamento & purificação , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Hematopoese/imunologia , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Malária/genética , Malária/imunologia , Malária/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Nódulos Linfáticos Agregados/imunologia , Extratos Vegetais/química , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium yoelii/efeitos dos fármacos , Plasmodium yoelii/crescimento & desenvolvimento , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
20.
Vet Microbiol ; 228: 69-76, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30593382

RESUMO

The porcine circovirus (PCV) is one of the most economically important infection diseases of pigs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) or Flic as an immune adjuvant has been shown to enhance the immunogenicity of vaccines in previous study. However, the composite biological adjuvants stimulate more effective immunological response. In this study, the porcine GM-CSF (pGM-CSF) and FliC protein were expressed by pSUMO in E.coli Rosetta (DE3) and purified by Ni-NTA Sepharose, respectively. The immunogenicity of PCV vaccine with pGM-CSF and FliC was firstly evaluated to identify the immunoenhancement in mice. The results indicated that mice immunized with vaccine + pGM-CSF + FliC enhanced immune responses ability significantly and quickly. Then, the immune response level of PCV vaccine with pGM-CSF and FliC was assessed in piglets. The results indicated that pigs immunized with vaccine + pGM-CSF + FliC showed significantly higher PCV antibody level than those immunized with vaccine and single adjuvant or vaccine alone. Furthermore, pigs in the vaccine + pGM-CSF + FliC group elicited stronger CD4+ and CD8 + T cells proliferative responses than those in all other groups and showed the effectively up-regulated transcriptional level of IL-1, IL-8 and IL-17 stimulating the immune system. We demonstrated that GM-CSF and FliC as composite biological adjuvants of the vaccine showed a stronger immune response and it is promising application for vaccines to against PCV.


Assuntos
Adjuvantes Imunológicos , Infecções por Circoviridae/veterinária , Circovirus/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Doenças dos Suínos/prevenção & controle , Vacinas Virais/imunologia , Animais , Infecções por Circoviridae/prevenção & controle , Infecções por Circoviridae/virologia , Feminino , Imunidade Humoral , Imunização/veterinária , Camundongos , Camundongos Endogâmicos BALB C , Suínos , Doenças dos Suínos/virologia
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