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[PMID]:29330050
[Au] Autor:Tanabe A; Nakano K; Nakakido M; Nagatoishi S; Tanaka Y; Tsumoto K; Uchimaru K; Watanabe T
[Ad] Endereço:Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
[Ti] Título:Production and characterization of a novel site-specific-modifiable anti-OX40-receptor single-chain variable fragment for targeted drug delivery.
[So] Source:Biochem Biophys Res Commun;496(2):614-620, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OX40 receptor (tumor necrosis factor receptor superfamily, member 4; CD134) is a T-cell co-stimulatory molecule that plays an important role in T-cell activation and survival. OX40 receptor is activated by its ligand, OX40L; and modulation of the OX40-OX40L interaction is a promising target for the treatment of autoimmune diseases and cancers. Here, we generated a high-affinity anti-OX40 single-chain variable fragment carrying a C-terminal cysteine residue (scFvC). Physicochemical and functional analyses revealed that the scFvC bound to OX40-expressing cells and was internalized via OX40-mediated endocytosis without inducing phosphorylation of IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), an important complex in the classical NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathway. In addition, mutation of the 36th cysteine residue in variable region of light chain enabled site-specific chemical modification to carboxy terminal cysteine and improved the thermal stability of the scFvC. These results suggest that this novel high-affinity anti-OX40 scFvC may be useful as a transporter for targeted delivery of small compounds, proteins, peptides, liposomes, and nanoparticles, into OX40-expressing cells for the treatment of autoimmune diseases and cancers.
[Mh] Termos MeSH primário: Imunoconjugados/imunologia
Receptores OX40/imunologia
Anticorpos de Cadeia Única/imunologia
[Mh] Termos MeSH secundário: Linhagem Celular
Sistemas de Liberação de Medicamentos
Escherichia coli/genética
Expressão Gênica
Seres Humanos
Imunoconjugados/química
Imunoconjugados/genética
Células Jurkat
Modelos Moleculares
Mutação Puntual
Estabilidade Proteica
Anticorpos de Cadeia Única/química
Anticorpos de Cadeia Única/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Immunoconjugates); 0 (Receptors, OX40); 0 (Single-Chain Antibodies)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE


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[PMID]:29352114
[Au] Autor:Rehage N; Davydova E; Conrad C; Behrens G; Maiser A; Stehklein JE; Brenner S; Klein J; Jeridi A; Hoffmann A; Lee E; Dianzani U; Willemsen R; Feederle R; Reiche K; Hackermüller J; Leonhardt H; Sharma S; Niessing D; Heissmeyer V
[Ad] Endereço:Institute for Immunology at the Biomedical Center, Ludwig-Maximilians-Universität München, Grosshaderner Strasse 9, 82152, Planegg-Martinsried, Germany.
[Ti] Título:Binding of NUFIP2 to Roquin promotes recognition and regulation of ICOS mRNA.
[So] Source:Nat Commun;9(1):299, 2018 01 19.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The ubiquitously expressed RNA-binding proteins Roquin-1 and Roquin-2 are essential for appropriate immune cell function and postnatal survival of mice. Roquin proteins repress target mRNAs by recognizing secondary structures in their 3'-UTRs and by inducing mRNA decay. However, it is unknown if other cellular proteins contribute to target control. To identify cofactors of Roquin, we used RNA interference to screen ~1500 genes involved in RNA-binding or mRNA degradation, and identified NUFIP2 as a cofactor of Roquin-induced mRNA decay. NUFIP2 binds directly and with high affinity to Roquin, which stabilizes NUFIP2 in cells. Post-transcriptional repression of human ICOS by endogenous Roquin proteins requires two neighboring non-canonical stem-loops in the ICOS 3'-UTR. This unconventional cis-element as well as another tandem loop known to confer Roquin-mediated regulation of the Ox40 3'-UTR, are bound cooperatively by Roquin and NUFIP2. NUFIP2 therefore emerges as a cofactor that contributes to mRNA target recognition by Roquin.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Proteínas Nucleares/genética
Proteínas de Ligação a RNA/genética
Receptores OX40/genética
Proteínas Repressoras/genética
Ubiquitina-Proteína Ligases/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Sítios de Ligação
Linfócitos T CD4-Positivos/citologia
Regulação da Expressão Gênica
Células HEK293
Células HeLa
Seres Humanos
Proteína Coestimuladora de Linfócitos T Induzíveis/antagonistas & inibidores
Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia
Sequências Repetidas Invertidas
Camundongos
Camundongos Endogâmicos C57BL
Proteínas Nucleares/antagonistas & inibidores
Proteínas Nucleares/imunologia
Conformação de Ácido Nucleico
Cultura Primária de Células
Ligação Proteica
Estabilidade de RNA
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Proteínas de Ligação a RNA/antagonistas & inibidores
Proteínas de Ligação a RNA/imunologia
Receptores OX40/antagonistas & inibidores
Receptores OX40/imunologia
Proteínas Recombinantes/genética
Proteínas Recombinantes/imunologia
Proteínas Repressoras/imunologia
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Ubiquitina-Proteína Ligases/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ICOS protein, human); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (NUFIP2 protein, human); 0 (Nuclear Proteins); 0 (RC3H1 protein, human); 0 (RNA, Small Interfering); 0 (RNA-Binding Proteins); 0 (Receptors, OX40); 0 (Recombinant Proteins); 0 (Repressor Proteins); 0 (TNFRSF4 protein, human); 0 (roquin-2 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180121
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02582-1


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[PMID]:28892135
[Au] Autor:Palmer CS; Duette GA; Wagner MCE; Henstridge DC; Saleh S; Pereira C; Zhou J; Simar D; Lewin SR; Ostrowski M; McCune JM; Crowe SM
[Ad] Endereço:Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.
[Ti] Título:Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection.
[So] Source:FEBS Lett;591(20):3319-3332, 2017 Oct.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:High glucose transporter 1 (Glut1) surface expression is associated with increased glycolytic activity in activated CD4+ T cells. Phosphatidylinositide 3-kinases (PI3K) activation measured by p-Akt and OX40 is elevated in CD4+Glut1+ T cells from HIV+ subjects. TCR engagement of CD4+Glut1+ T cells from HIV+ subjects demonstrates hyperresponsive PI3K-mammalian target of rapamycin signaling. High basal Glut1 and OX40 on CD4+ T cells from combination antiretroviral therapy (cART)-treated HIV+ patients represent a sufficiently metabolically active state permissive for HIV infection in vitro without external stimuli. The majority of CD4+OX40+ T cells express Glut1, thus OX40 rather than Glut1 itself may facilitate HIV infection. Furthermore, infection of CD4+ T cells is limited by p110γ PI3K inhibition. Modulating glucose metabolism may limit cellular activation and prevent residual HIV replication in 'virologically suppressed' cART-treated HIV+ persons.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/uso terapêutico
Linfócitos T CD4-Positivos/metabolismo
Transportador de Glucose Tipo 1/imunologia
Infecções por HIV/metabolismo
Receptores OX40/imunologia
[Mh] Termos MeSH secundário: Adulto
Terapia Antirretroviral de Alta Atividade
Linfócitos T CD4-Positivos/efeitos dos fármacos
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/virologia
Proliferação Celular
Classe Ib de Fosfatidilinositol 3-Quinase/antagonistas & inibidores
Classe Ib de Fosfatidilinositol 3-Quinase/genética
Classe Ib de Fosfatidilinositol 3-Quinase/imunologia
Regulação da Expressão Gênica
Transportador de Glucose Tipo 1/genética
Infecções por HIV/tratamento farmacológico
Infecções por HIV/imunologia
Infecções por HIV/virologia
HIV-1/efeitos dos fármacos
HIV-1/crescimento & desenvolvimento
Seres Humanos
Ativação Linfocitária
Masculino
Cultura Primária de Células
Inibidores de Proteínas Quinases/farmacologia
Proteínas Proto-Oncogênicas c-akt/genética
Proteínas Proto-Oncogênicas c-akt/imunologia
Receptores OX40/genética
Transdução de Sinais
Serina-Treonina Quinases TOR/genética
Serina-Treonina Quinases TOR/imunologia
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (Glucose Transporter Type 1); 0 (Protein Kinase Inhibitors); 0 (Receptors, OX40); 0 (SLC2A1 protein, human); 0 (TNFRSF4 protein, human); EC 2.7.1.1 (MTOR protein, human); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.1.137 (Class Ib Phosphatidylinositol 3-Kinase); EC 2.7.1.137 (PIK3CG protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12843


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[PMID]:28796044
[Au] Autor:Chen J; Li JH; Zhao SJ; Wang DY; Zhang WZ; Liang WJ
[Ad] Endereço:aDepartment of Cardiovascular Medicine, Guangzhou Panyu Central Hospital, bPanyu District Cardiovascular Disease Research Institute of Guangzhou, Guangzhou, P.R. China.
[Ti] Título:Clinical significance of costimulatory molecules CD40/CD40L and CD134/CD134L in coronary heart disease: A case-control study.
[So] Source:Medicine (Baltimore);96(32):e7634, 2017 Aug.
[Is] ISSN:1536-5964
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The aim of the study was to evaluate the potential role of CD40/CD40 ligand (CD40L) and CD134/CD134 ligand (CD134L) in the development of coronary heart disease (CHD) via the performance of a case-control study.The research objects were 234 cases of CHD patients and 120 cases of well-matched normal controls. Following the separation of peripheral blood mononuclear cells (PBMCs), real-time quantitative PCR (qRT-PCR), Western blot, immunohistochemistry, and flow cytometry were applied for the detection of mRNA levels and expression levels of CD40/CD40L and CD134/CD134L; meanwhile, intercellular adhesion molecule-1 (ICAM-1) and Fas protein mRNA levels were detected using qRT-PCR.There was no statistical difference in the comparison of baseline characteristics between groups, indicating comparability between groups. qRT-PCR and Western blot analysis indicated that CD40/CD40L and CD134/CD134L mRNA and protein expression levels were all increased in the CHD group than those in the control group. Flow cytometry further confirmed the similar tendency. Meanwhile, ICAM-1 and Fas protein mRNA levels were elevated in the CHD group and positively correlated with the above parameters. Furthermore, CD40/CD40L expression rates were negatively correlated with gender and different types of CHD. Meanwhile, CD134/CD134L expressions were also higher in male patients, in patients with family history, previous history of hypertension, diabetes, and cerebrovascular diseases.CD40/CD40L and CD134/CD134L are increased and may have potential correlation with clinical pathological features of patients with CHD. Further in-depth exploration of costimulatory molecules for CHD guidance as well as intrinsic mechanisms are needed combined with in vivo and in vitro experiments.
[Mh] Termos MeSH primário: Antígenos CD40/biossíntese
Ligante de CD40/biossíntese
Doença das Coronárias/fisiopatologia
Ligante OX40/biossíntese
Receptores OX40/biossíntese
[Mh] Termos MeSH secundário: Adulto
Idoso
Estudos de Casos e Controles
Feminino
Citometria de Fluxo
Seres Humanos
Molécula 1 de Adesão Intercelular/biossíntese
Masculino
Meia-Idade
RNA Mensageiro
Reação em Cadeia da Polimerase em Tempo Real
Receptor fas/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (CD40 Antigens); 0 (FAS protein, human); 0 (OX40 Ligand); 0 (RNA, Messenger); 0 (Receptors, OX40); 0 (fas Receptor); 126547-89-5 (Intercellular Adhesion Molecule-1); 147205-72-9 (CD40 Ligand)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1097/MD.0000000000007634


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[PMID]:28733709
[Au] Autor:Ito SE; Shirota H; Kasahara Y; Saijo K; Ishioka C
[Ad] Endereço:Department of Clinical Oncology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
[Ti] Título:IL-4 blockade alters the tumor microenvironment and augments the response to cancer immunotherapy in a mouse model.
[So] Source:Cancer Immunol Immunother;66(11):1485-1496, 2017 Nov.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Recent findings show that immune cells constitute a large fraction of the tumor microenvironment and that they modulate tumor progression. Clinical data indicate that chronic inflammation is present at tumor sites and that IL-4, in particular, is upregulated. Thus, we tested whether IL-4 neutralization would affect tumor immunity. Current results demonstrate that the administration of a neutralizing antibody against IL-4 enhances anti-tumor immunity and delays tumor progression. IL-4 blockade also alters inflammation in the tumor microenvironment, reducing the generation of both immunosuppressive M2 macrophages and myeloid-derived suppressor cells, and enhancing tumor-specific cytotoxic T lymphocytes. In addition, IL-4 blockade improves the response to anti-OX40 Ab or CpG oligodeoxynucleotide immunotherapies. These findings suggest that IL-4 affects anti-tumor immunity and constitutes an attractive therapeutic target to reduce immune suppression in the tumor microenvironment, thus enhancing the efficacy of cancer therapy.
[Mh] Termos MeSH primário: Anticorpos Neutralizantes/farmacologia
Imunoterapia/métodos
Interleucina-4/antagonistas & inibidores
Neoplasias Experimentais/terapia
Microambiente Tumoral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Anticorpos Neutralizantes/imunologia
Linhagem Celular Tumoral
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/imunologia
Interleucina-4/genética
Interleucina-4/imunologia
Macrófagos/classificação
Macrófagos/efeitos dos fármacos
Macrófagos/imunologia
Camundongos Endogâmicos BALB C
Neoplasias Experimentais/imunologia
Neoplasias Experimentais/patologia
Oligodesoxirribonucleotídeos/imunologia
Oligodesoxirribonucleotídeos/farmacologia
Receptores OX40/antagonistas & inibidores
Receptores OX40/imunologia
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Linfócitos T Citotóxicos/efeitos dos fármacos
Linfócitos T Citotóxicos/imunologia
Fatores de Tempo
Resultado do Tratamento
Carga Tumoral/efeitos dos fármacos
Carga Tumoral/genética
Carga Tumoral/imunologia
Microambiente Tumoral/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (CPG-oligonucleotide); 0 (Oligodeoxyribonucleotides); 0 (Receptors, OX40); 207137-56-2 (Interleukin-4)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE
[do] DOI:10.1007/s00262-017-2043-6


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[PMID]:28696253
[Au] Autor:Sitrin J; Suto E; Wuster A; Eastham-Anderson J; Kim JM; Austin CD; Lee WP; Behrens TW
[Ad] Endereço:Department of Human Genetics, Genentech, Inc., South San Francisco, CA 94080; sitrinjr@gmail.com.
[Ti] Título:The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice.
[So] Source:J Immunol;199(4):1238-1249, 2017 Aug 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ox40 ligand (Ox40L) locus genetic variants are associated with the risk for systemic lupus erythematosus (SLE); however, it is unclear how Ox40L contributes to SLE pathogenesis. In this study, we evaluated the contribution of Ox40L and its cognate receptor, Ox40, using in vivo agonist and antagonist approaches in the NZB × NZW (NZB/W) F1 mouse model of SLE. Ox40 was highly expressed on several CD4 Th cell subsets in the spleen and kidney of diseased mice, and expression correlated with disease severity. Treatment of aged NZB/W F1 mice with agonist anti-Ox40 mAbs potently exacerbated renal disease, which was accompanied by activation of kidney-infiltrating T cells and cytokine production. The agonist mAbs also induced activation and inflammatory gene expression in splenic CD4 T cells, including IFN-regulated genes, increased the number of follicular helper T cells and plasmablasts in the spleen, and led to elevated levels of serum IgM and enhanced renal glomerular IgM deposition. In a type I IFN-accelerated lupus model, treatment with an antagonist Ox40:Fc fusion protein significantly delayed the onset of severe proteinuria and improved survival. These data support the hypothesis that the Ox40/Ox40L pathway drives cellular and humoral autoimmune responses during lupus nephritis in NZB/W F1 mice and emphasize the potential clinical value of targeting this pathway in human lupus.
[Mh] Termos MeSH primário: Nefrite Lúpica/imunologia
Glicoproteínas de Membrana/metabolismo
Plasmócitos/imunologia
Receptores OX40/metabolismo
Linfócitos T Auxiliares-Indutores/imunologia
Fatores de Necrose Tumoral/metabolismo
[Mh] Termos MeSH secundário: Animais
Anticorpos Antinucleares/imunologia
Anticorpos Monoclonais/imunologia
Autoimunidade
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/metabolismo
Modelos Animais de Doenças
Feminino
Seres Humanos
Rim/imunologia
Rim/patologia
Glomérulos Renais/imunologia
Glomérulos Renais/patologia
Nefrite Lúpica/fisiopatologia
Camundongos
Camundongos Endogâmicos NZB
Proteinúria/imunologia
Transdução de Sinais
Linfócitos T Auxiliares-Indutores/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Antinuclear); 0 (Antibodies, Monoclonal); 0 (Membrane Glycoproteins); 0 (Receptors, OX40); 0 (Tnfrsf4 protein, mouse); 0 (Tnfsf4 protein, mouse); 0 (Tumor Necrosis Factors)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700608


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[PMID]:28648384
[Au] Autor:Long AE; Tatum M; Mikacenic C; Buckner JH
[Ad] Endereço:Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
[Ti] Título:A novel and rapid method to quantify Treg mediated suppression of CD4 T cells.
[So] Source:J Immunol Methods;449:15-22, 2017 Oct.
[Is] ISSN:1872-7905
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Measuring regulatory T cell suppression provides important insight into T cell dysfunction in autoimmune disease. However, to date, suppression assays are limited by the requirement for freshly isolated cells, and significant cell numbers. Here, we present a novel and rapid in vitro assay using effector T cell surface expression of both CD25 and CD134 as a surrogate marker of regulatory T cell-mediated suppression. This surface marker-based suppression assay works for frozen samples and for samples with limited cell numbers. It is also shorter taking two days to complete compared to the four days required for proliferation-based assays. Furthermore, this assay works with both in vitro expanded and natural Tregs, as well as anti-CD3/anti-CD28 bead-based and APC stimulation conditions. In conclusion, we have developed and validated a new suppression assay for cryopreserved samples with limited cell numbers that may be helpful to investigate T cell regulation in the context of infection or autoimmune diseases.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Linfócitos T CD4-Positivos/fisiologia
Proliferação Celular
Seres Humanos
Subunidade alfa de Receptor de Interleucina-2/genética
Subunidade alfa de Receptor de Interleucina-2/imunologia
Ativação Linfocitária
Receptores OX40/genética
Receptores OX40/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (IL2RA protein, human); 0 (Interleukin-2 Receptor alpha Subunit); 0 (Receptors, OX40); 0 (TNFRSF4 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170627
[St] Status:MEDLINE


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[PMID]:28646041
[Au] Autor:Nawaf MG; Ulvmar MH; Withers DR; McConnell FM; Gaspal FM; Webb GJ; Jones ND; Yagita H; Allison JP; Lane PJL
[Ad] Endereço:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom.
[Ti] Título:Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity.
[So] Source:J Immunol;199(3):974-981, 2017 Aug 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell-driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3 mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell-driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.
[Mh] Termos MeSH primário: Autoimunidade
Ligante CD30/antagonistas & inibidores
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD8-Positivos/imunologia
Antígeno CTLA-4/antagonistas & inibidores
Neoplasias/imunologia
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Receptores OX40/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Ligante CD30/imunologia
Antígeno CTLA-4/imunologia
Fatores de Transcrição Forkhead/deficiência
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Imunoterapia
Ligantes
Ativação Linfocitária
Camundongos
Camundongos Knockout
Neoplasias/terapia
Receptor de Morte Celular Programada 1/imunologia
Receptores OX40/imunologia
Linfócitos T Reguladores/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD30 Ligand); 0 (CTLA-4 Antigen); 0 (Ctla4 protein, mouse); 0 (Forkhead Transcription Factors); 0 (Foxp3 protein, mouse); 0 (Ligands); 0 (Programmed Cell Death 1 Receptor); 0 (Receptors, OX40)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700088


  9 / 583 MEDLINE  
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[PMID]:28436935
[Au] Autor:Lan P; Fan Y; Zhao Y; Lou X; Monsour HP; Zhang X; Choi Y; Dou Y; Ishii N; Ghobrial RM; Xiao X; Li XC
[Ad] Endereço:Immunobiology and Transplant Science Center, Houston Methodist Research Institute, and.
[Ti] Título:TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury.
[So] Source:J Clin Invest;127(6):2222-2234, 2017 Jun 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A-induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro-IL-1ß to mature IL-1ß as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore-forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Células T Matadoras Naturais/fisiologia
Piroptose
Receptores OX40/fisiologia
[Mh] Termos MeSH secundário: Animais
Caspase 1/metabolismo
Caspases/metabolismo
Linhagem Celular
Doença Hepática Induzida por Substâncias e Drogas/patologia
Ativação Enzimática
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa
Proteínas de Neoplasias/metabolismo
Transporte Proteico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (Receptors, OX40); 0 (Tnfrsf4 protein, mouse); EC 3.4.22.- (Caspases); EC 3.4.22.- (Malt1 protein, mouse); EC 3.4.22.- (Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein); EC 3.4.22.36 (Caspase 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE


  10 / 583 MEDLINE  
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[PMID]:28432083
[Au] Autor:Shinde P; Liu W; Ménoret A; Luster AD; Vella AT
[Ad] Endereço:Department of Immunology, School of Medicine, University of Connecticut Health, Farmington, Connecticut, USA.
[Ti] Título:Optimal CD4 T cell priming after LPS-based adjuvanticity with CD134 costimulation relies on CXCL9 production.
[So] Source:J Leukoc Biol;102(1):57-69, 2017 Jul.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:LPS is a powerful adjuvant, and although LPS-mediated TLR4 signaling has been exquisitely delineated, the in vivo mechanism of how TLR4 responses impact T cell priming is far less clear. Besides costimulation, TNF and type 1 IFN are dominant cytokines released after TLR4 activation and can shape T cell responses, but other downstream factors have not been examined extensively. Depending on context, we show that IFNαR1 blockade resulted in minor to major effects on specific CD4 T cell clonal expansion. To help explain these differences, it was hypothesized that IFNαR1 blockade would inhibit specific T cell migration by reducing chemokine receptor signaling, but specific CD4 T cells from IFNαR1-blocked mice were readily able to migrate in response to specific chemokines. Next, we examined downstream factors and found that type 1 IFN signaling was necessary for chemokine production, even when mice were immunized with specific Ag with LPS and CD134 costimulation. IFNαR1 signaling promoted CXCL9 and CXCL10 synthesis, suggesting that these chemokines might be involved in the LPS and CD134 costimulation response. After immunization, we show that CXCL9 blockade inhibited CD4 T cell accumulation in the liver but also in LNs, even in the presence of elevated serum IFN-ß levels. Thus, whereas type 1 IFN might have direct effects on primed CD4 T cells, the downstream chemokines that play a role during migration also impact accumulation. In sum, CXCL9 production is a key benchmark for productive CD4 T cell vaccination strategies.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Proliferação Celular/efeitos dos fármacos
Quimiocina CXCL9/imunologia
Lipopolissacarídeos/farmacologia
Receptores OX40/imunologia
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Quimiocina CXCL10/genética
Quimiocina CXCL10/imunologia
Quimiocina CXCL9/genética
Interferon beta/genética
Interferon beta/imunologia
Camundongos
Camundongos Knockout
Receptor de Interferon alfa e beta/genética
Receptor de Interferon alfa e beta/imunologia
Receptores OX40/genética
Transdução de Sinais/genética
Transdução de Sinais/imunologia
Receptor 4 Toll-Like/genética
Receptor 4 Toll-Like/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chemokine CXCL10); 0 (Chemokine CXCL9); 0 (Cxcl10 protein, mouse); 0 (Cxcl9 protein, mouse); 0 (Ifnar1 protein, mouse); 0 (Lipopolysaccharides); 0 (Receptors, OX40); 0 (Tlr4 protein, mouse); 0 (Tnfrsf4 protein, mouse); 0 (Toll-Like Receptor 4); 156986-95-7 (Receptor, Interferon alpha-beta); 77238-31-4 (Interferon-beta)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171014
[Lr] Data última revisão:
171014
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170423
[St] Status:MEDLINE
[do] DOI:10.1189/jlb.1A0616-261RR



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