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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

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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

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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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