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Pesquisa : D12.776.543.750.705.222.812 [Categoria DeCS]
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[PMID]:28922790
[Au] Autor:Marisa L; Svrcek M; Collura A; Becht E; Cervera P; Wanherdrick K; Buhard O; Goloudina A; Jonchère V; Selves J; Milano G; Guenot D; Cohen R; Colas C; Laurent-Puig P; Olschwang S; Lefèvre JH; Parc Y; Boige V; Lepage C; André T; Fléjou JF; Dérangère V; Ghiringhelli F; de Reynies A; Duval A
[Ad] Endereço:Programme "Cartes d'Identité des Tumeurs," Ligue Nationale Contre le Cancer, Paris, France; INSERM, UMRS 938 - Centre de Recherche Saint-Antoine, Equipe "Instabilité des Microsatellites et Cancers," Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France; Sorbonne Université, UPMC U
[Ti] Título:The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors.
[So] Source:J Natl Cancer Inst;110(1), 2018 Jan 01.
[Is] ISSN:1460-2105
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Background: Immune checkpoint (ICK) expression might represent a surrogate measure of tumor-infiltrating T cell (CTL) exhaustion and therefore be a more accurate prognostic biomarker for colorectal cancer (CRC) patients than CTL enumeration as measured by the Immunoscore. Methods: The expression of ICKs, Th1, CTLs, cytotoxicity-related genes, and metagenes, including Immunoscore-like metagenes, were evaluated in three independent cohorts of CRC samples (260 microsatellite instable [MSI], 971 non-MSI). Their associations with patient survival were analyzed by Cox models, taking into account the microsatellite instability (MSI) status and affiliation with various Consensus Molecular Subgroups (CMS). PD-L1 and CD8 expression were examined on a subset of tumors with immunohistochemistry. All statistical tests were two-sided. Results: The expression of Immunoscore-like metagenes was statistically significantly associated with improved outcome in non-MSI tumors displaying low levels of both CTLs and immune checkpoints (ICKs; CMS2 and CMS3; hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.43 to 0.92, P = .02; and HR = 0.55, 95% CI = 0.34 to 0.90, P = .02, respectively), but clearly had no prognostic relevance in CRCs displaying higher levels of CTLs and ICKs (CMS1 and CMS4; HR = 0.46, 95% CI = 0.10 to 2.10, P = .32; and HR = 1.13, 95% CI = 0.79 to 1.63, P = .50, respectively), including MSI tumors. ICK metagene expression was statistically significantly associated with worse prognosis independent of tumor staging in MSI tumors (HR = 3.46, 95% CI = 1.41 to 8.49, P = .007). ICK expression had a negative impact on the proliferation of infiltrating CD8 T cells in MSI neoplasms (median = 0.56 in ICK low vs median = 0.34 in ICK high, P = .004). Conclusions: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Biomarcadores Tumorais/imunologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/imunologia
Linfócitos do Interstício Tumoral
Linfócitos T Citotóxicos
[Mh] Termos MeSH secundário: Antígenos CD/genética
Antígeno B7-H1/análise
Antígeno B7-H1/genética
Antígenos CD8/análise
Antígeno CTLA-4/genética
Colo/química
Neoplasias Colorretais/química
Neoplasias Colorretais/patologia
Feminino
Expressão Gênica
Receptor Celular 2 do Vírus da Hepatite A/genética
Seres Humanos
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Masculino
Instabilidade de Microssatélites
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Proteína 2 Ligante de Morte Celular Programada 1/genética
Receptor de Morte Celular Programada 1/genética
Estudos Retrospectivos
Taxa de Sobrevida
Células Th1
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antigens, CD); 0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD223 antigen); 0 (CD274 protein, human); 0 (CD8 Antigens); 0 (CTLA-4 Antigen); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (ICOS protein, human); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (PDCD1LG2 protein, human); 0 (Programmed Cell Death 1 Ligand 2 Protein); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180308
[Lr] Data última revisão:
180308
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1093/jnci/djx136


  2 / 703 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


  3 / 703 MEDLINE  
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[PMID]:28466476
[Au] Autor:Li H; Hao Y; Zhang D; Liu W; Li Y; Lyu M; Fu R; Xue F; Liu X; Yang R
[Ad] Endereço:State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
[Ti] Título:Numerical and functional defects in CD8 CD28 T-suppressor lymphocytes from patients with primary immune thrombocytopenia.
[So] Source:Br J Haematol;178(2):292-301, 2017 07.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8 CD28 suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8 CD28 CD127 proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8 CD28 Ts cells in ITP patients was impaired. Mechanistic studies have shown that CD8 CD28 Ts cells from controls can downregulate CD80 and upregulate LILRB4 (ITL3) and LILRB2 (ILT4) expression on CD14 monocytes, whereas these abilities were not found in Ts cells from ITP patients. Furthermore, Inducible T-cell costimulatory (ICOS) expression on the Ts cell surface after activation was decreased whereas programmed death 1 and interleukin 10 expression was not changed in ITP patients compared with those of controls. In summary, the down-regulated quantity and function of Ts cells in active patients indicated that a Ts defect was involved in ITP. Moreover, decreased ICOS expression and the loss of the ability to regulate co-stimulator expression on antigen-presenting cells partly explained the defective Ts-mediated suppression.
[Mh] Termos MeSH primário: Antígenos CD28/metabolismo
Linfócitos T CD8-Positivos/fisiologia
Púrpura Trombocitopênica Idiopática/imunologia
Linfócitos T Reguladores/fisiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Citocinas/metabolismo
Feminino
Seres Humanos
Tolerância Imunológica/fisiologia
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Interferon gama/biossíntese
Interleucina-10/fisiologia
Subpopulações de Linfócitos/fisiologia
Masculino
Meia-Idade
Receptor de Morte Celular Programada 1/metabolismo
Fator de Crescimento Transformador beta1/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CD28 Antigens); 0 (Cytokines); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 0 (Transforming Growth Factor beta1); 130068-27-8 (Interleukin-10); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14661


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[PMID]:28748530
[Au] Autor:Sebina I; Fogg LG; James KR; Soon MSF; Akter J; Thomas BS; Hill GR; Engwerda CR; Haque A
[Ad] Endereço:QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
[Ti] Título:IL-6 promotes CD4 T-cell and B-cell activation during Plasmodium infection.
[So] Source:Parasite Immunol;39(10), 2017 Oct.
[Is] ISSN:1365-3024
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Humoral immunity develops in the spleen during blood-stage Plasmodium infection. This elicits parasite-specific IgM and IgG, which control parasites and protect against malaria. Studies in mice have elucidated cells and molecules driving humoral immunity to Plasmodium, including CD4 T cells, B cells, interleukin (IL)-21 and ICOS. IL-6, a cytokine readily detected in Plasmodium-infected mice and humans, is recognized in other systems as a driver of humoral immunity. Here, we examined the effect of infection-induced IL-6 on humoral immunity to Plasmodium. Using P. chabaudi chabaudi AS (PcAS) infection of wild-type and IL-6 mice, we found that IL-6 helped to control parasites during primary infection. IL-6 promoted early production of parasite-specific IgM but not IgG. Notably, splenic CD138 plasmablast development was more dependent on IL-6 than germinal centre (GC) B-cell differentiation. IL-6 also promoted ICOS expression by CD4 T cells, as well as their localization close to splenic B cells, but was not required for early Tfh-cell development. Finally, IL-6 promoted parasite control, IgM and IgG production, GC B-cell development and ICOS expression by Tfh cells in a second model, Py17XNL infection. IL-6 promotes CD4 T-cell activation and B-cell responses during blood-stage Plasmodium infection, which encourages parasite-specific antibody production.
[Mh] Termos MeSH primário: Linfócitos B/imunologia
Linfócitos T CD4-Positivos/imunologia
Interleucina-6/imunologia
Ativação Linfocitária/imunologia
Malária/imunologia
Plasmodium chabaudi/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Antiprotozoários/imunologia
Citocinas/metabolismo
Feminino
Imunidade Humoral/imunologia
Imunoglobulina G/imunologia
Imunoglobulina M/imunologia
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Interleucina-6/genética
Interleucinas/imunologia
Malária/parasitologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Baço/imunologia
Sindecana-1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Protozoan); 0 (Cytokines); 0 (Icos protein, mouse); 0 (Immunoglobulin G); 0 (Immunoglobulin M); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Interleukin-6); 0 (Interleukins); 0 (Sdc1 protein, mouse); 0 (Syndecan-1); 0 (interleukin-21); 0 (interleukin-6, mouse)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1111/pim.12455


  5 / 703 MEDLINE  
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[PMID]:28916523
[Au] Autor:Kamekura R; Takano K; Yamamoto M; Kawata K; Shigehara K; Jitsukawa S; Nagaya T; Ito F; Sato A; Ogasawara N; Tsubomatsu C; Takahashi H; Nakase H; Himi T; Ichimiya S
[Ad] Endereço:Department of Human Immunology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo 060-8556, Japan; rkameku@sapmed.ac.jp.
[Ti] Título:Cutting Edge: A Critical Role of Lesional T Follicular Helper Cells in the Pathogenesis of IgG4-Related Disease.
[So] Source:J Immunol;199(8):2624-2629, 2017 Oct 15.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:IgG4-related disease (IgG4-RD) is a newly recognized systemic chronic fibroinflammatory disease. However, the pathogenesis of IgG4-RD remains unknown. To determine the pathophysiologic features of IgG4-RD, we examined T follicular helper (Tfh) cells in lesions and blood from patients with IgG4-RD. Patients with IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) showed increased infiltration of Tfh cells highly expressing programmed death 1 and ICOS in submandibular glands. Tfh cells from IgG4-DS submandibular glands had higher expression of B cell lymphoma 6 and a greater capacity to help B cells produce IgG4 than did tonsillar Tfh cells. We also found that the percentage of programmed death 1 circulating Tfh cells in IgG4-DS patients was higher than that in healthy volunteers and was well correlated with clinical parameters. Our findings indicate that anomalous Tfh cells in tissue lesions of IgG4-RD have features distinct from those in lymphoid counterparts or blood and potentially regulate local IgG4 production in IgG4-RD.
[Mh] Termos MeSH primário: Doenças Autoimunes/imunologia
Linfócitos B/imunologia
Dacriocistite/imunologia
Imunoglobulina G/metabolismo
Receptor de Morte Celular Programada 1/metabolismo
Glândula Submandibular/imunologia
Linfócitos T Auxiliares-Indutores/imunologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Movimento Celular
Células Cultivadas
Feminino
Seres Humanos
Imunoglobulina G/imunologia
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Ativação Linfocitária
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ICOS protein, human); 0 (Immunoglobulin G); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601507


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[PMID]:28652395
[Au] Autor:Gullicksrud JA; Li F; Xing S; Zeng Z; Peng W; Badovinac VP; Harty JT; Xue HH
[Ad] Endereço:Department of Microbiology, University of Iowa, Iowa City, IA 52242.
[Ti] Título:Differential Requirements for Tcf1 Long Isoforms in CD8 and CD4 T Cell Responses to Acute Viral Infection.
[So] Source:J Immunol;199(3):911-919, 2017 Aug 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In response to acute viral infection, activated naive T cells give rise to effector T cells that clear the pathogen and memory T cells that persist long-term and provide heightened protection. T cell factor 1 (Tcf1) is essential for several of these differentiation processes. Tcf1 is expressed in multiple isoforms, with all isoforms sharing the same HDAC and DNA-binding domains and the long isoforms containing a unique N-terminal ß-catenin-interacting domain. In this study, we specifically ablated Tcf1 long isoforms in mice, while retaining expression of Tcf1 short isoforms. During CD8 T cell responses, Tcf1 long isoforms were dispensable for generating cytotoxic CD8 effector T cells and maintaining memory CD8 T cell pool size, but they contributed to optimal maturation of central memory CD8 T cells and their optimal secondary expansion in a recall response. In contrast, Tcf1 long isoforms were required for differentiation of T follicular helper (T ) cells, but not T 1 effectors, elicited by viral infection. Although Tcf1 short isoforms adequately supported Bcl6 and ICOS expression in T cells, Tcf1 long isoforms remained important for suppressing the expression of Blimp1 and T 1-associated genes and for positively regulating Id3 to restrain germinal center T cell differentiation. Furthermore, formation of memory T 1 and memory T cells strongly depended on Tcf1 long isoforms. These data reveal that Tcf1 long and short isoforms have distinct, yet complementary, functions and may represent an evolutionarily conserved means to ensure proper programming of CD8 and CD4 T cell responses to viral infection.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD8-Positivos/imunologia
Coriomeningite Linfocítica/imunologia
Vírus da Coriomeningite Linfocítica/imunologia
Fator 1 de Transcrição de Linfócitos T/química
Fator 1 de Transcrição de Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Testes Imunológicos de Citotoxicidade
Centro Germinativo/citologia
Centro Germinativo/imunologia
Centro Germinativo/metabolismo
Memória Imunológica
Proteína Coestimuladora de Linfócitos T Induzíveis/genética
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Proteínas Inibidoras de Diferenciação/genética
Proteínas Inibidoras de Diferenciação/metabolismo
Vírus da Coriomeningite Linfocítica/isolamento & purificação
Camundongos
Fator 1 de Ligação ao Domínio I Regulador Positivo
Isoformas de Proteínas
Proteínas Proto-Oncogênicas c-bcl-6/genética
Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
Fator 1 de Transcrição de Linfócitos T/deficiência
Fator 1 de Transcrição de Linfócitos T/genética
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bcl6 protein, mouse); 0 (Icos protein, mouse); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Inhibitor of Differentiation Proteins); 0 (Prdm1 protein, mouse); 0 (Protein Isoforms); 0 (Proto-Oncogene Proteins c-bcl-6); 0 (T Cell Transcription Factor 1); 0 (Transcription Factors); 135845-89-5 (Idb3 protein, mouse); EC 2.1.1.- (Positive Regulatory Domain I-Binding Factor 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700595


  7 / 703 MEDLINE  
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[PMID]:28622456
[Au] Autor:Blokland SLM; Hillen MR; Kruize AA; Meller S; Homey B; Smithson GM; Radstake TRDJ; van Roon JAG
[Ad] Endereço:University Medical Center Utrecht, Utrecht, The Netherlands.
[Ti] Título:Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis.
[So] Source:Arthritis Rheumatol;69(10):2038-2051, 2017 Oct.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjögren's syndrome (SS). CCR9-expressing T helper cells have "Tfh-like" characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS. METHODS: Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties. RESULTS: CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor α-chain (IL-7Rα). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7Rα and secreted higher levels of interferon-γ, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells. CONCLUSION: Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.
[Mh] Termos MeSH primário: Quimiocinas CC/imunologia
Glândulas Salivares Menores/imunologia
Síndrome de Sjogren/imunologia
Linfócitos T Auxiliares-Indutores/imunologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Autoimunidade/imunologia
Linfócitos B/imunologia
Estudos de Casos e Controles
Quimiocinas CC/genética
Feminino
Seres Humanos
Imunoglobulina G/imunologia
Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia
Interferon gama/imunologia
Interleucina-17/imunologia
Interleucina-4/imunologia
Subunidade alfa de Receptor de Interleucina-7/imunologia
Interleucinas/imunologia
Lábio
Masculino
Meia-Idade
Receptor de Morte Celular Programada 1/imunologia
RNA Mensageiro
Receptores CCR/imunologia
Receptores CXCR5/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CC chemokine receptor 9); 0 (CCL25 protein, human); 0 (CXCR5 protein, human); 0 (Chemokines, CC); 0 (IL4 protein, human); 0 (Immunoglobulin G); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Interleukin-17); 0 (Interleukin-7 Receptor alpha Subunit); 0 (Interleukins); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 0 (RNA, Messenger); 0 (Receptors, CCR); 0 (Receptors, CXCR5); 0 (interleukin-21); 207137-56-2 (Interleukin-4); 82115-62-6 (Interferon-gamma)
[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:170617
[St] Status:MEDLINE
[do] DOI:10.1002/art.40182


  8 / 703 MEDLINE  
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[PMID]:28502093
[Au] Autor:Shalaby KH; Al Heialy S; Tsuchiya K; Farahnak S; McGovern TK; Risse PA; Suh WK; Qureshi ST; Martin JG
[Ad] Endereço:Department of Medicine, Meakins-Christie Laboratories, McGill University Health Centre Research Institute, McGill University, Montréal, QC, Canada.
[Ti] Título:The TLR4-TRIF pathway can protect against the development of experimental allergic asthma.
[So] Source:Immunology;152(1):138-149, 2017 Sep.
[Is] ISSN:1365-2567
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Toll-like receptor (TLR) adaptor proteins myeloid differentiating factor 88 (MyD88) and Toll, interleukin-1 receptor and resistance protein (TIR) domain-containing adaptor inducing interferon-ß (TRIF) comprise the two principal limbs of the TLR signalling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4 ICOS T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and TLR4 agonists. Wild-type (WT), Trif or Myd88 mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF deficiency diminished the CD4 ICOS T-cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF deficiency reduced the proportion of cervical lymph node and lung CD4 ICOS Foxp3 cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4 ICOS cells in the TRIF-dependent inhibition of airway hyper-responsiveness. Hence, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4 ICOS T-cell responses may be a contributing mechanism.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/metabolismo
Asma/prevenção & controle
Linfócitos T CD4-Positivos/metabolismo
Pulmão/metabolismo
Rinite Alérgica Sazonal/prevenção & controle
Receptor 4 Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/genética
Proteínas Adaptadoras de Transporte Vesicular/imunologia
Transferência Adotiva
Animais
Antígenos de Plantas/imunologia
Asma/imunologia
Asma/metabolismo
Asma/fisiopatologia
Betula/imunologia
Hiper-Reatividade Brônquica/imunologia
Hiper-Reatividade Brônquica/metabolismo
Hiper-Reatividade Brônquica/fisiopatologia
Hiper-Reatividade Brônquica/prevenção & controle
Broncoconstrição
Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD4-Positivos/transplante
Proliferação Celular
Quimiotaxia de Leucócito
Cisteína Endopeptidases/imunologia
Modelos Animais de Doenças
Combinação de Medicamentos
Feminino
Predisposição Genética para Doença
Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Lipopolissacarídeos/imunologia
Pulmão/imunologia
Pulmão/fisiopatologia
Ativação Linfocitária
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Camundongos Knockout
Fator 88 de Diferenciação Mieloide/genética
Fator 88 de Diferenciação Mieloide/metabolismo
Fenótipo
Pólen/imunologia
Rinite Alérgica Sazonal/imunologia
Rinite Alérgica Sazonal/metabolismo
Rinite Alérgica Sazonal/fisiopatologia
Transdução de Sinais
Fatores de Tempo
Receptor 4 Toll-Like/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (Antigens, Plant); 0 (Drug Combinations); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Lipopolysaccharides); 0 (Myd88 protein, mouse); 0 (Myeloid Differentiation Factor 88); 0 (Protollin); 0 (TICAM-1 protein, mouse); 0 (Tlr4 protein, mouse); 0 (Toll-Like Receptor 4); EC 3.4.22.- (Cysteine Endopeptidases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170515
[St] Status:MEDLINE
[do] DOI:10.1111/imm.12755


  9 / 703 MEDLINE  
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[PMID]:28428203
[Au] Autor:Pattarini L; Trichot C; Bogiatzi S; Grandclaudon M; Meller S; Keuylian Z; Durand M; Volpe E; Madonna S; Cavani A; Chiricozzi A; Romanelli M; Hori T; Hovnanian A; Homey B; Soumelis V
[Ad] Endereço:Institut Curie, PSL Research University, Institut National de la Santé et de la Recherche Médicale (INSERM), U932, F-75005 Paris, France vassili.soumelis@curie.fr lucia.pattarini@curie.fr.
[Ti] Título:TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand.
[So] Source:J Exp Med;214(5):1529-1546, 2017 May 01.
[Is] ISSN:1540-9538
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:T follicular helper cells (Tfh) are important regulators of humoral responses. Human Tfh polarization pathways have been thus far associated with Th1 and Th17 polarization pathways. How human Tfh cells differentiate in Th2-skewed environments is unknown. We show that thymic stromal lymphopoietin (TSLP)-activated dendritic cells (DCs) promote human Tfh differentiation from naive CD4 T cells. We identified a novel population, distinct from Th2 cells, expressing IL-21 and TNF, suggestive of inflammatory cells. TSLP-induced T cells expressed CXCR5, CXCL13, ICOS, PD1, BCL6, BTLA, and SAP, among other Tfh markers. Functionally, TSLP-DC-polarized T cells induced IgE secretion by memory B cells, and this depended on IL-4Rα. TSLP-activated DCs stimulated circulating memory Tfh cells to produce IL-21 and CXCL13. Mechanistically, TSLP-induced Tfh differentiation depended on OX40-ligand, but not on ICOS-ligand. Our results delineate a pathway of human Tfh differentiation in Th2 environments.
[Mh] Termos MeSH primário: Citocinas/fisiologia
Células Dendríticas/fisiologia
Ligante OX40/fisiologia
Células Th2/fisiologia
[Mh] Termos MeSH secundário: Diferenciação Celular/fisiologia
Quimiocina CXCL13/metabolismo
Seres Humanos
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Interleucinas/metabolismo
Receptor de Morte Celular Programada 1/metabolismo
Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
Receptores CXCR5/metabolismo
Receptores Imunológicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL6 protein, human); 0 (BTLA protein, human); 0 (CXCL13 protein, human); 0 (CXCR5 protein, human); 0 (Chemokine CXCL13); 0 (Cytokines); 0 (ICOS protein, human); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (Interleukins); 0 (OX40 Ligand); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 0 (Proto-Oncogene Proteins c-bcl-6); 0 (Receptors, CXCR5); 0 (Receptors, Immunologic); 0 (interleukin-21); 0 (thymic stromal lymphopoietin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE
[do] DOI:10.1084/jem.20150402


  10 / 703 MEDLINE  
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[PMID]:28335888
[Au] Autor:Dempke WCM; Fenchel K; Uciechowski P; Dale SP
[Ad] Endereço:Kyowa Kirin Pharmaceutical Development, Galashiels, United Kingdom; University of Munich, University Hospital of Grosshadern, Department of Haematology and Oncology, Germany. Electronic address: wolfram.dempke@kyowakirin.com.
[Ti] Título:Second- and third-generation drugs for immuno-oncology treatment-The more the better?
[So] Source:Eur J Cancer;74:55-72, 2017 Mar.
[Is] ISSN:1879-0852
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Recent success in cancer immunotherapy (anti-CTLA-4, anti-PD1/PD-L1) has confirmed the hypothesis that the immune system can control many cancers across various histologies, in some cases producing durable responses in a way not seen with many small-molecule drugs. However, only less than 25% of all patients do respond to immuno-oncology drugs and several resistance mechanisms have been identified (e.g. T-cell exhaustion, overexpression of caspase-8 and ß-catenin, PD-1/PD-L1 gene amplification, MHC-I/II mutations). To improve response rates and to overcome resistance, novel second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I/II trials (either alone or in combination) including novel inhibitory compounds (e.g. TIM-3, VISTA, LAG-3, IDO, KIR) and newly developed co-stimulatory antibodies (e.g. CD40, GITR, OX40, CD137, ICOS). It is important to note that co-stimulatory agents strikingly differ in their proposed mechanism of action compared with monoclonal antibodies that accomplish immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1/PD-1 or others. Indeed, the prospect of combining agonistic with antagonistic agents is enticing and represents a real immunologic opportunity to 'step on the gas' while 'cutting the brakes', although this strategy as a novel cancer therapy has not been universally endorsed so far. Concerns include the prospect of triggering cytokine-release syndromes, autoimmune reactions and hyper immune stimulation leading to activation-induced cell death or tolerance, however, toxicity has not been a major issue in the clinical trials reported so far. Although initial phase I/II clinical trials of agonistic and novel antagonistic drugs have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy or other immune system targeting drugs; however, numerous questions remain about dose, schedule, route of administration and formulation as well as identifying the appropriate patient populations. In our view, with such a wealth of potential mechanisms of action and with the ability to fine-tune monoclonal antibody structure and function to suit particular requirements, the second and third wave of immuno-oncology drugs are likely to provide rapid advances with new combinations of novel immunotherapy (especially co-stimulatory antibodies). Here, we will review the mechanisms of action and the clinical data of these new antibodies and discuss the major issues facing this rapidly evolving field.
[Mh] Termos MeSH primário: Anticorpos Monoclonais Humanizados/uso terapêutico
Antineoplásicos/uso terapêutico
Imunoterapia/métodos
Neoplasias/terapia
[Mh] Termos MeSH secundário: Antígenos CD/efeitos dos fármacos
Linfócitos B/imunologia
Antígenos B7/antagonistas & inibidores
Antígenos B7/imunologia
Antígenos CD40/agonistas
Antígeno CTLA-4/antagonistas & inibidores
Citocinas/imunologia
Proteína Relacionada a TNFR Induzida por Glucocorticoide/efeitos dos fármacos
Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores
Seres Humanos
Imunidade Celular/fisiologia
Indolamina-Pirrol 2,3,-Dioxigenase/antagonistas & inibidores
Proteína Coestimuladora de Linfócitos T Induzíveis/agonistas
Células Matadoras Naturais/imunologia
Ativação Linfocitária/imunologia
Complexo Principal de Histocompatibilidade/imunologia
Neoplasias/imunologia
Ligante OX40/agonistas
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Receptores KIR/antagonistas & inibidores
Subpopulações de Linfócitos T/imunologia
Linfócitos T Citotóxicos/imunologia
Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antibodies, Monoclonal, Humanized); 0 (Antigens, CD); 0 (Antineoplastic Agents); 0 (B7 Antigens); 0 (CD223 antigen); 0 (CD40 Antigens); 0 (CTLA-4 Antigen); 0 (Cytokines); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (ICOS protein, human); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (OX40 Ligand); 0 (Programmed Cell Death 1 Receptor); 0 (Receptors, KIR); 0 (TNFRSF18 protein, human); 0 (TNFRSF9 protein, human); 0 (TNFSF4 protein, human); 0 (Tumor Necrosis Factor Receptor Superfamily, Member 9); 0 (VISTA protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE



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