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1.
Nat Immunol ; 19(12): 1319-1329, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30397348

RESUMO

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.


Assuntos
Adenocarcinoma/imunologia , Macrófagos/imunologia , Melanoma/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Acidose/imunologia , Adenocarcinoma/metabolismo , Animais , Neoplasias do Colo/imunologia , Neoplasias do Colo/metabolismo , Glicólise/imunologia , Humanos , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
2.
Eur J Cancer ; 59: 160-170, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27039171

RESUMO

The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient's tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies.


Assuntos
Neoplasias Gastrointestinais/terapia , Imunoterapia/tendências , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Métodos Epidemiológicos , Previsões , Marcadores Genéticos/fisiologia , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Terapia Viral Oncolítica/métodos , Resultado do Tratamento
3.
Food Chem ; 138(1): 263-9, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23265486

RESUMO

Lipid transfer proteins (LTP) play a major role in plant defence and are of particular interest due to their known ability to cause allergic reactions. These proteins are expressed in grapes and also remain detectable after vinification, especially in red wine. However, it remains unknown whether the protein undergoes any changes during the vinification process. Here, we present a purification method for LTPs from Dornfelder grapes and wine. By liquid-chromatography-mass spectroscopy (LC-MS/MS) we identified LTPs from two different species (Vitis vinifera and Vitis aestivalis). Additionally, the purified LTPs were characterised using spectrometric methods, confirming their high purity and structural stability during vinification. We conclude that LTPs are resistant to the alcohol content (13.5 vol%), acidic milieu of wine and other ingredients present during the vinification process, indicating that the allergenic potential of grape LTP is not diminished by the vinification process.


Assuntos
Proteínas de Transporte/química , Proteínas de Transporte/isolamento & purificação , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Vitis/química , Vinho/análise , Conformação Proteica , Espectrometria de Massas em Tandem
4.
Cancer Immunol Immunother ; 59(8): 1273-84, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20419298

RESUMO

Immune surveillance of tumour cells by CD8(+) cytotoxic T cells plays a key role in the establishment and control of an anti-tumour response. This process requires the generation of antigenic peptides, which are largely produced by the proteasome in combination with other proteases located in either the cytoplasm and/or the endoplasmic reticulum (ER). The ER-resident aminopeptidases ERAP1 and ERAP2 trim or even destroy HLA class I-binding peptides thereby shaping the peptide repertoire presented for T cell recognition. So far there exists limited information about the expression pattern of ERAP1 and/or ERAP2 in human tumours of distinct histotypes. Therefore, the expression profiles and modes of regulation of both aminopeptidases were determined in a large series of melanoma cell lines. A heterogeneous expression ranging from high to reduced or even total loss of ERAP1 and/or ERAP2 mRNA and/or protein expression was detected, which often could be induced/upregulated by interferon-gamma treatment. The observed altered ERAP1 and/or ERAP2 expression and activity levels were either mediated by sequence alterations affecting the promoter or enzymatic activities, leading to either transcriptional and/or post-transcriptional downregulation mechanisms or limited or excessive processing activities, which both might have an impact on the antigenic peptide repertoire presented on HLA class I molecules.


Assuntos
Aminopeptidases/metabolismo , Antígenos de Neoplasias/metabolismo , Retículo Endoplasmático/enzimologia , Melanoma/enzimologia , Regiões 5' não Traduzidas/genética , Aminopeptidases/genética , Aminopeptidases/imunologia , Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Clonagem Molecular , Retículo Endoplasmático/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Humanos , Interferon gama/farmacologia , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Antígenos de Histocompatibilidade Menor , Mutagênese Sítio-Dirigida
5.
Dev Comp Immunol ; 34(7): 722-33, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20100511

RESUMO

Allergens from cockroaches cause major asthma-related health problems worldwide. Among them Per a 3 belongs to the most potent allergens. Although the sequences of some members of the Per a 3-family are known, their biochemical and biophysical properties have not been investigated. Here we present for the first time a thorough structural characterization of these allergens, which have recently been tested to induce an increase of allergy specific indicators in blood of Europeans. We isolated two Per a 3 isoforms, which occur freely dissolved in the hemolymph as hexamers with molecular masses of 465+/-25kDa (P II) and 512+/-25kDa (P I). Their sedimentation coefficients (S(20,W)) were determined to be 17.4+/-0.7 S (P II) and 19.0+/-0.9 S (P I), respectively. Sequence analysis revealed that P II consists of two subunit types known as allergens Per a 3.01 and Per a 3.0201, while PI consists of a new allergenic subunit type designated as Per a 3.03. A 3D model of the hexameric allergen Per a 3 was obtained by homology modelling. Almost all of the recently predicted 11 putative antigenic peptides and reported IgE-epitopes could be located on the surface of the hexamer, thus being freely accessible in the hexameric structure of the native molecules. We propose this might contribute to their allergic potential as well as their extreme stability with respect to temperature.


Assuntos
Alérgenos/imunologia , Alérgenos/isolamento & purificação , Proteínas de Insetos/imunologia , Proteínas de Insetos/isolamento & purificação , Periplaneta/imunologia , Alérgenos/química , Alérgenos/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Dicroísmo Circular , Eletroforese em Gel de Poliacrilamida , Proteínas de Insetos/química , Proteínas de Insetos/genética , Espectrometria de Massas , Microscopia Eletrônica , Microscopia de Fluorescência , Modelos Moleculares , Dados de Sequência Molecular , Isoformas de Proteínas , Alinhamento de Sequência , Análise de Sequência de DNA , Ultracentrifugação
6.
J Agric Food Chem ; 57(10): 4328-33, 2009 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-19385597

RESUMO

Wine proteins not only influence wine stability but are also being discussed as potential allergens. Proteins from red, rosé, and white wines were enriched by dialysis and lyophilization followed by separation by SDS-PAGE. Significant differences were detected in the protein compositions of the analyzed wine varieties, and the major protein bands were identified by mass spectrometry after in-gel digestion with trypsin. In German Portugieser red wine, a total of 121 tryptic peptides were identified, which were attributed to 12 grape proteins and 6 proteins derived from yeast. Among the identified constituents are several proteins considered to influence wine stability and previously described potential grape allergens. The pathogenesis-related proteins represent the main proteins in all of the wines, but only some red wines show a band with a molecular mass of 12 kDa, identified as a lipid transfer protein (LTP). The occurrence and distribution of LTP depend on the wine variety.


Assuntos
Cromatografia Líquida de Alta Pressão , Eletroforese , Espectrometria de Massas , Proteínas/análise , Vinho/análise , Alérgenos/análise , Antígenos de Plantas/análise , Antígenos de Plantas/imunologia , Proteínas de Transporte/análise , Proteínas de Transporte/imunologia , Hipersensibilidade Alimentar , Frutas/química , Proteínas Fúngicas/análise , Proteínas de Plantas/análise , Proteínas de Plantas/imunologia , Tripsina/metabolismo , Vitis/química
7.
Br J Haematol ; 125(3): 392-9, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15086422

RESUMO

Invasive aspergillosis (IA) is a leading cause of mortality in haematological patients. Appropriate activation of the innate immune system is crucial for the successful clearance of IA. Therefore, we studied the Aspergillus fumigatus-mediated activation of human granulocytes and monocyte-derived immature dendritic cells (DCs), as well as murine bone marrow-derived DCs (BMDCs) from wild type, toll-like receptor (TLR)4-deficient, TLR2 knockout, and TLR2/TLR4 double deficient mice. Aspergillus fumigatus antigens induced the activation and maturation of immature DCs as characterized by CD83 expression, upregulation of major histocompatibility complex and co-stimulatory molecules. Moreover, fungal antigens enhanced the phagocytosis and production of interleukin (IL)-8 in granulocytes. The release of IL-12 by BMDCs in response to A. fumigatus antigens was dependent on the expression of TLR2, whereas the release of IL-6 was dependent on the expression of functional TLR4 molecules. The protein precipitate of A. fumigatus supernatant provided strong stimulation of DCs and granulocytes, indicating that a factor secreted by A. fumigatus might activate innate immune cells. In conclusion, A. fumigatus antigens induced the activation of DCs and granulocytes. Our results indicated that this activation was mediated via TLR2 and TLR4. Future studies are needed to assess the clinical impact of these findings in patients at high risk for IA.


Assuntos
Antígenos de Fungos/imunologia , Aspergillus fumigatus/imunologia , Glicoproteínas de Membrana/imunologia , Receptores de Superfície Celular/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Humanos , Imunidade Celular , Interleucinas/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Receptores de Superfície Celular/genética , Receptor 2 Toll-Like , Receptor 4 Toll-Like , Receptores Toll-Like
8.
Blood ; 101(7): 2810-5, 2003 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-12446445

RESUMO

The endoplasmic reticulum (ER)-resident heat shock protein Gp96 is involved in protein folding and is released into the extracellular space after necrotic cell death. In this context, Gp96 has immunostimulatory properties: it activates dendritic cells or macrophages and delivers associated peptides into the antigen presentation pathway, resulting in the induction of specific T-cell responses. The inflammatory response after necrotic tissue damage leads to the recruitment of polymorphonuclear neutrophils (PMNs) and monocytes, allowing them to make their first encounter with Gp96. We therefore investigated whether PMNs and monocytes interact with Gp96. We were able to show that PMNs and monocytes specifically bind fluorescein isothiocyanate (FITC)-conjugated Gp96. The binding of Gp96-FITC was competed by lipopolysaccharide (LPS) or fucoidan, a known inhibitor of scavenger receptors. Interestingly, the binding of LPS-FITC was also competed not only by fucoidan, but by Gp96, suggesting that LPS and Gp96 share a common receptor on PMNs. One important effector function of PMNs is the clearance of an inflammatory site by phagocytosis. We therefore assessed the influence of Gp96 on phagocytic activity using fluorochrome-labeled polystyrene beads. We found a marked enhancement of phagocytosis in the presence of Gp96 and concluded that PMNs not only bind Gp96, but are also activated by it. Additionally, Gp96-stimulated PMNs and especially monocytes release large amounts of interleukin-8, a potent neutrophil-attracting chemokine. In conclusion, we demonstrate that Gp96 specifically binds to and activates PMNs and monocytes, extending the function of Gp96 as a danger signal to additional members of the innate immune system.


Assuntos
Antígenos de Neoplasias/metabolismo , Monócitos/metabolismo , Neutrófilos/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/farmacologia , Citometria de Fluxo , Fluoresceína-5-Isotiocianato , Humanos , Interleucina-8/biossíntese , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Ligação Proteica/imunologia
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