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  1 / 8167 MEDLINE  
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[PMID]:29253009
[Au] Autor:Hafstrand I; Badia-Martinez D; Josey BJ; Norström M; Buratto J; Pellegrino S; Duru AD; Sandalova T; Achour A
[Ad] Endereço:Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, and Department of Infectious Diseases, Karolinska University Hospital, Solna, Stockholm, Sweden.
[Ti] Título:Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity.
[So] Source:PLoS One;12(12):e0189584, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Post-translational modifications significantly broaden the epitope repertoire for major histocompatibility class I complexes (MHC-I) and may allow viruses to escape immune recognition. Lymphocytic choriomeningitis virus (LCMV) infection of H-2b mice generates CD8+ CTL responses directed towards several MHC-I-restricted epitopes including the peptides GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL), both with a N-glycosylation site. Interestingly, glycosylation has different effects on the immunogenicity and association capacity of these two epitopes to H-2Db. To assess the structural bases underlying these functional results, we determined the crystal structures of H-2Db in complex with GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL) to 2.4 and 2.5 Å resolution, respectively. The structures reveal that while glycosylation of GP392 most probably impairs binding, the glycosylation of the asparagine residue in GP92, which protrudes towards the solvent, possibly allows for immune escape and/or forms a neo-epitope that may select for a different set of CD8 T cells. Altogether, the presented results provide a structural platform underlying the effects of post-translational modifications on epitope binding and/or immunogenicity, resulting in viral immune escape.
[Mh] Termos MeSH primário: Apresentação do Antígeno
Antígenos Virais/imunologia
Antígenos H-2/imunologia
Vírus da Coriomeningite Linfocítica/imunologia
[Mh] Termos MeSH secundário: Animais
Asparagina/química
Linfócitos T CD8-Positivos/metabolismo
Cristalografia por Raios X
Epitopos/imunologia
Glicosilação
Camundongos
Peptídeos/imunologia
Processamento de Proteína Pós-Traducional
Solventes
Linfócitos T Citotóxicos/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Viral); 0 (Epitopes); 0 (H-2 Antigens); 0 (Peptides); 0 (Solvents); 7006-34-0 (Asparagine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171219
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189584


  2 / 8167 MEDLINE  
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[PMID]:27933274
[Au] Autor:Ma RX; Cheng LF; Ying QK; Liu RR; Ma TJ; Zhang XX; Liu ZY; Zhang L; Ye W; Zhang FL; Xu ZK; Wang F; Wu XA
[Ad] Endereço:Department of Microbiology, School of Basic Medicine, Fourth Military Medical University Xi'an, China.
[Ti] Título:Screening and Identification of an H-2K -Restricted CTL Epitope within the Glycoprotein of Hantaan Virus.
[So] Source:Front Cell Infect Microbiol;6:151, 2016.
[Is] ISSN:2235-2988
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:The cytotoxic T lymphocyte (CTL) response plays a key role in controlling viral infection, but only a few epitopes within the HTNV glycoprotein (GP) that are recognized by CTLs have been reported. In this study, we identified one murine HTNV GP-derived H2-K -restricted CTL epitope in C57BL/6 mice, which could be used to design preclinical studies of vaccines for HTNV infection. First, 15 8-mer peptides were selected from the HTNV GP amino acid sequence based on a percentile rank of <=1% by IEDB which is the most comprehensive collection of epitope prediction and analysis tool. A lower percentile rank indicates higher affinity and higher immune response. In the case of the consensus method, we also evaluated the binding score of peptide-binding affinity by the BIMAS software to confirm that all peptides were able to bind H2-K . Second, one novel GP-derived CTL epitope, GP6 aa456-aa463 (ITSLFSLL), was identified in the splenocytes of HTNV-infected mice using the IFN-γ ELISPOT assay. Third, a single peptide vaccine was administered to C57BL/6 mice to evaluate the immunogenic potential of the identified peptides. ELISPOT and cell-mediated cytotoxicity assays showed that this peptide vaccine induced a strong IFN-γ response and potent cytotoxicity in immunized mice. Last, we demonstrated that the peptide-vaccinated mice had partial protection from challenge with HTNV. In conclusion, we identified an H2-K -restricted CTL epitope with involvement in the host immune response to HTNV infection.
[Mh] Termos MeSH primário: Epitopos de Linfócito T/imunologia
Antígenos H-2/isolamento & purificação
Antígenos H-2/farmacologia
Vírus Hantaan/imunologia
Febre Hemorrágica com Síndrome Renal/prevenção & controle
Linfócitos T Citotóxicos/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Antígenos Virais/análise
Antígenos Virais/imunologia
Linfócitos T CD4-Positivos
Linfócitos T CD8-Positivos
Linhagem Celular
Citocinas/análise
Testes Imunológicos de Citotoxicidade
Modelos Animais de Doenças
ELISPOT/métodos
Feminino
Glicoproteínas/efeitos dos fármacos
Glicoproteínas/imunologia
Vírus Hantaan/genética
Vírus Hantaan/patogenicidade
Febre Hemorrágica com Síndrome Renal/virologia
Imunização
Interferon gama/análise
Camundongos
Camundongos Endogâmicos C57BL
RNA Viral/isolamento & purificação
Baço/imunologia
Baço/patologia
Vacinas de Subunidades/imunologia
Vacinas Sintéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Viral); 0 (Cytokines); 0 (Epitopes, T-Lymphocyte); 0 (Glycoproteins); 0 (H-2 Antigens); 0 (H-2Kb protein, mouse); 0 (RNA, Viral); 0 (Vaccines, Subunit); 0 (Vaccines, Synthetic); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE


  3 / 8167 MEDLINE  
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[PMID]:27667124
[Au] Autor:Kajiwara T; Tanaka T; Kukita K; Kutomi G; Saito K; Okuya K; Takaya A; Kochin V; Kanaseki T; Tsukahara T; Hirohashi Y; Torigoe T; Hirata K; Sato N; Tamura Y
[Ad] Endereço:Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
[Ti] Título:Hypoxia augments MHC class I antigen presentation via facilitation of ERO1-α-mediated oxidative folding in murine tumor cells.
[So] Source:Eur J Immunol;46(12):2842-2851, 2016 Dec.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:To establish an effective cancer immunotherapy, it is crucial that cancer cells present a cancer-specific antigen in a hypoxic area, a hallmark of the tumor microenvironment. Here, we show the impact of hypoxia on MHC class I antigen presentation in vitro and in vivo in murine tumors. Activation of antigen-specific CTLs by tumor cells that had been pre-incubated under a condition of hypoxia was enhanced compared with that by tumor cells pre-incubated under a condition of normoxia. Cell surface expression of MHC class I-peptide complex on the tumor cells was increased under a condition of hypoxia, thereby leading to higher susceptibility to specific CTLs. We show that the hypoxia-inducible ER-resident oxidase ERO1-α plays an important role in the hypoxia-induced augmentation of MHC class I-peptide complex expression. ERO1-α facilitated oxidative folding of MHC class I heavy chains, thereby resulting in the augmentation of cell surface expression of MHC class I-peptide complex under hypoxic conditions. These results suggest that since the expression of MHC class I-peptide complex is augmented in a hypoxic tumor microenvironment, strategies for inhibiting the function of regulatory T cells and myeloid-derived suppressor cells and/or immunotherapy with immune checkpoint inhibitors are promising for improving cancer immunotherapy.
[Mh] Termos MeSH primário: Glicoproteínas/metabolismo
Hipóxia/imunologia
Imunoterapia/métodos
Melanoma/imunologia
Linfócitos T Citotóxicos/imunologia
[Mh] Termos MeSH secundário: Animais
Apresentação do Antígeno
Modelos Animais de Doenças
Feminino
Antígenos H-2/metabolismo
Seres Humanos
Hipóxia/terapia
Melanoma/terapia
Melanoma Experimental
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Oxirredução
Dobramento de Proteína
Linfócitos T Citotóxicos/transplante
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ero1l protein, mouse); 0 (Glycoproteins); 0 (H-2 Antigens); 0 (H-2Kb protein, mouse)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170705
[Lr] Data última revisão:
170705
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160927
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201646525


  4 / 8167 MEDLINE  
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[PMID]:27435737
[Au] Autor:Frietze KK; Pappy AL; Melson JW; O'Driscoll EE; Tyler CM; Perlman DH; Boulanger LM
[Ad] Endereço:Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
[Ti] Título:Cryptic protein-protein interaction motifs in the cytoplasmic domain of MHCI proteins.
[So] Source:BMC Immunol;17(1):24, 2016 Jul 19.
[Is] ISSN:1471-2172
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Major histocompatibility complex class I (MHCI) proteins present antigenic peptides for immune surveillance and play critical roles in nervous system development and plasticity. Most MHCI are transmembrane proteins. The extracellular domain of MHCI interacts with immunoreceptors, peptides, and co-receptors to mediate immune signaling. While the cytoplasmic domain also plays important roles in endocytic trafficking, cross-presentation of extracellularly derived antigens, and CTL priming, the molecular mediators of cytoplasmic signaling by MHCI remain largely unknown. RESULTS: Here we show that the cytoplasmic domain of MHCI contains putative protein-protein interaction domains known as PDZ (PSD95/disc large/zonula occludens-1) ligands. PDZ ligands are motifs that bind to PDZ domains to organize and mediate signaling at cell-cell contacts. PDZ ligands are short, degenerate motifs, and are therefore difficult to identify via sequence homology alone, but several lines of evidence suggest that putative PDZ ligand motifs in MHCI are under positive selective pressure. Putative PDZ ligands are found in all of the 99 MHCI proteins examined from diverse species, and are enriched in the cytoplasmic domain, where PDZ interactions occur. Both the position of the PDZ ligand and the class of ligand motif are conserved across species, as well as among genes within a species. Non-synonymous substitutions, when they occur, frequently preserve the motif. Of the many specific possible PDZ ligand motifs, a handful are strikingly and selectively overrepresented in MHCI's cytoplasmic domain, but not elsewhere in the same proteins. Putative PDZ ligands in MHCI encompass conserved serine and tyrosine residues that are targets of phosphorylation, a post-translational modification that can regulate PDZ interactions. Finally, proof-of-principle in vitro interaction assays demonstrate that the cytoplasmic domains of particular MHCI proteins can bind directly and specifically to PDZ1 and PDZ4&5 of MAGI-1, and identify a conserved PDZ ligand motif in the classical MHCI H2-K that is required for this interaction. CONCLUSIONS: These results identify cryptic protein interaction motifs in the cytoplasmic domain of MHCI. In so doing, they suggest that the cytoplasmic domain of MHCI could participate in previously unsuspected PDZ mediated protein-protein interactions at neuronal as well as immunological synapses.
[Mh] Termos MeSH primário: Motivos de Aminoácidos/genética
Citoplasma/metabolismo
Antígenos H-2/metabolismo
Antígenos HLA/metabolismo
Sinapses Imunológicas/metabolismo
Sistema Nervoso/imunologia
Domínios PDZ/genética
Domínios e Motivos de Interação entre Proteínas/genética
[Mh] Termos MeSH secundário: Animais
Apresentação do Antígeno
Antígenos H-2/genética
Antígenos HLA/genética
Seres Humanos
Vigilância Imunológica
Camundongos
Fosforilação
Análise de Sequência de Proteína
Serina
Transdução de Sinais
Tirosina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (H-2 Antigens); 0 (H-2Kb protein, mouse); 0 (HLA Antigens); 42HK56048U (Tyrosine); 452VLY9402 (Serine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160721
[St] Status:MEDLINE
[do] DOI:10.1186/s12865-016-0154-z


  5 / 8167 MEDLINE  
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[PMID]:27385590
[Au] Autor:Sullivan LC; Berry R; Sosnin N; Widjaja JM; Deuss FA; Balaji GR; LaGruta NL; Mirams M; Trapani JA; Rossjohn J; Brooks AG; Andrews DM
[Ad] Endereço:From the Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
[Ti] Título:Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C.
[So] Source:J Biol Chem;291(36):18740-52, 2016 09 02.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 µm) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both ∼1 µm), and this recognition could be prevented by cis interactions with H-2K in situ To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated ß2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2K(b) Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2K(b) possess similar energetic footprints focused around residues located within the Ly49C ß4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules.
[Mh] Termos MeSH primário: Antígeno de Histocompatibilidade H-2D/química
Células Matadoras Naturais/química
Subfamília A de Receptores Semelhantes a Lectina de Células NK/química
[Mh] Termos MeSH secundário: Animais
Cristalografia por Raios X
Antígenos H-2/química
Antígenos H-2/genética
Antígenos H-2/imunologia
Antígeno de Histocompatibilidade H-2D/genética
Antígeno de Histocompatibilidade H-2D/imunologia
Células Matadoras Naturais/imunologia
Camundongos
Camundongos Knockout
Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética
Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia
Domínios Proteicos
Estrutura Quaternária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (H-2 Antigens); 0 (H-2Kb protein, mouse); 0 (Histocompatibility Antigen H-2D); 0 (Klra3 protein, mouse); 0 (NK Cell Lectin-Like Receptor Subfamily A)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160708
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.737130


  6 / 8167 MEDLINE  
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[PMID]:27092794
[Au] Autor:Pritchard GH; Cross EW; Strobel M; Jameson SC; Kedl RM; Hogquist KA; Hunter CA
[Ad] Endereço:Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
[Ti] Título:Spontaneous partial loss of the OT-I transgene.
[So] Source:Nat Immunol;17(5):471, 2016 May.
[Is] ISSN:1529-2916
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/imunologia
Antígenos H-2/imunologia
Ovalbumina/imunologia
Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Linfócitos T CD8-Positivos/metabolismo
Citometria de Fluxo
Antígenos H-2/metabolismo
Camundongos Transgênicos
Ovalbumina/genética
Ovalbumina/metabolismo
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/imunologia
Fragmentos de Peptídeos/metabolismo
Reação em Cadeia da Polimerase
Receptores de Antígenos de Linfócitos T alfa-beta/genética
Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
Especificidade do Receptor de Antígeno de Linfócitos T/imunologia
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (H-2 Antigens); 0 (H-2Kb protein, mouse); 0 (OVA-8); 0 (Peptide Fragments); 0 (Receptors, Antigen, T-Cell, alpha-beta); 9006-59-1 (Ovalbumin)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160420
[St] Status:MEDLINE
[do] DOI:10.1038/ni.3411


  7 / 8167 MEDLINE  
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[PMID]:27070447
[Au] Autor:Kastánková I; Poláková I; Dusková M; Smahel M
[Ad] Endereço:*Institute of Hematology and Blood Transfusion †Faculty of Science, Charles University in Prague, Prague, Czech Republic.
[Ti] Título:Combined Cancer Immunotherapy Against Aurora Kinase A.
[So] Source:J Immunother;39(4):160-70, 2016 May.
[Is] ISSN:1537-4513
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aurora kinase A (AURKA) is a centrosomal protein that is overexpressed in a number of human malignancies and can contribute to tumor progression. As we used this protein as a target of DNA immunization, we increased its immunogenicity by the addition of the PADRE helper epitope and decreased its potential oncogenicity by mutagenesis of the kinase domain. For in vitro analysis of induced immune responses in mice, we identified the Aurka(220-228) nonapeptide representing an H-2Kb epitope. As DNA vaccination against the Aurka self-antigen by a gene gun did not show any antitumor effect, we combined DNA immunization with anti-CD25 treatment that depletes mainly regulatory T cells. Whereas 1 anti-CD25 dose injected before DNA vaccination did not enhance the activation of Aurka-specific splenocytes, 3 doses administered on days of immunizations augmented about 10-fold immunity against Aurka. However, an opposite effect was found for antitumor immunity-only 1 anti-CD25 dose combined with DNA vaccination reduced tumor growth. Moreover, the administration of 3 doses of anti-CD25 antibody alone accelerated tumor growth. Analysis of tumor-infiltrating cells showed that 3 anti-CD25 doses not only efficiently depleted regulatory T cells but also activated helper T cells and CD3(-)CD25(+) cells. Next, we found that blockade of the PD-1 receptor initiated 1 week after the first immunization was necessary for significant inhibition of tumor growth with therapeutic DNA vaccination against Aurka combined with depletion of CD25 cells. Our results suggest that combined cancer immunotherapy should be carefully evaluated to achieve the optimal antitumor effect.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/uso terapêutico
Aurora Quinase A/metabolismo
Linfócitos T CD8-Positivos/imunologia
Vacinas Anticâncer/imunologia
Epitopos de Linfócito T/metabolismo
Imunoterapia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Animais
Aurora Quinase A/genética
Aurora Quinase A/imunologia
Processos de Crescimento Celular/efeitos dos fármacos
Terapia Combinada
Epitopos de Linfócito T/genética
Epitopos de Linfócito T/imunologia
Feminino
Antígenos H-2/metabolismo
Células HEK293
Seres Humanos
Imunização
Subunidade alfa de Receptor de Interleucina-2/imunologia
Ativação Linfocitária
Camundongos
Camundongos Endogâmicos C57BL
Receptor de Morte Celular Programada 1/antagonistas & inibidores
Vacinas de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Cancer Vaccines); 0 (Epitopes, T-Lymphocyte); 0 (H-2 Antigens); 0 (H-2Kb protein, mouse); 0 (Interleukin-2 Receptor alpha Subunit); 0 (Programmed Cell Death 1 Receptor); 0 (Vaccines, DNA); EC 2.7.11.1 (Aurora Kinase A)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160413
[St] Status:MEDLINE
[do] DOI:10.1097/CJI.0000000000000120


  8 / 8167 MEDLINE  
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[PMID]:26847142
[Au] Autor:Laubreton D; Bay S; Sedlik C; Artaud C; Ganneau C; Dériaud E; Viel S; Puaux AL; Amigorena S; Gérard C; Lo-Man R; Leclerc C
[Ad] Endereço:Unité de Régulation Immunitaire et Vaccinologie, Equipe Labellisée Ligue Contre le Cancer, Institut Pasteur, 25 rue du Docteur Roux, 75015, Paris, France.
[Ti] Título:The fully synthetic MAG-Tn3 therapeutic vaccine containing the tetanus toxoid-derived TT830-844 universal epitope provides anti-tumor immunity.
[So] Source:Cancer Immunol Immunother;65(3):315-25, 2016 Mar.
[Is] ISSN:1432-0851
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.
[Mh] Termos MeSH primário: Antígenos Glicosídicos Associados a Tumores/imunologia
Linfócitos T CD4-Positivos/imunologia
Vacinas Anticâncer/imunologia
Epitopos de Linfócito T/imunologia
Glicoproteína Associada a Mielina/imunologia
Fragmentos de Peptídeos/imunologia
Toxoide Tetânico/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Feminino
Antígenos H-2/genética
Cadeias HLA-DRB1/imunologia
Haplótipos
Seres Humanos
Macaca fascicularis
Camundongos
Camundongos Endogâmicos
Dados de Sequência Molecular
Vacinação
Vacinas Sintéticas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Tumor-Associated, Carbohydrate); 0 (Cancer Vaccines); 0 (Epitopes, T-Lymphocyte); 0 (H-2 Antigens); 0 (HLA-DRB1 Chains); 0 (MAG protein, human); 0 (Myelin-Associated Glycoprotein); 0 (Peptide Fragments); 0 (Tetanus Toxoid); 0 (Tn antigen); 0 (Vaccines, Synthetic)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:160320
[Lr] Data última revisão:
160320
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160206
[St] Status:MEDLINE
[do] DOI:10.1007/s00262-016-1802-0


  9 / 8167 MEDLINE  
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[PMID]:26716832
[Au] Autor:Liao TY; Lau A; Joseph S; Hytönen V; Hmama Z
[Ad] Endereço:Division of Infectious Diseases, Department of Medicine and Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
[Ti] Título:Improving the Immunogenicity of the Mycobacterium bovis BCG Vaccine by Non-Genetic Bacterial Surface Decoration Using the Avidin-Biotin System.
[So] Source:PLoS One;10(12):e0145833, 2015.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Current strategies to improve the current BCG vaccine attempt to over-express genes encoding specific M. tuberculosis (Mtb) antigens and/or regulators of antigen presentation function, which indeed have the potential to reshape BCG in many ways. However, these approaches often face serious difficulties, in particular the efficiency and stability of gene expression via nucleic acid complementation and safety concerns associated with the introduction of exogenous DNA. As an alternative, we developed a novel non-genetic approach for rapid and efficient display of exogenous proteins on bacterial cell surface. The technology involves expression of proteins of interest in fusion with a mutant version of monomeric avidin that has the feature of reversible binding to biotin. Fusion proteins are then used to decorate the surface of biotinylated BCG. Surface coating of BCG with recombinant proteins was highly reproducible and stable. It also resisted to the freeze-drying shock routinely used in manufacturing conventional BCG. Modifications of BCG surface did not affect its growth in culture media neither its survival within the host cell. Macrophages phagocytized coated BCG bacteria, which efficiently delivered their surface cargo of avidin fusion proteins to MHC class I and class II antigen presentation compartments. Thereafter, chimeric proteins corresponding to a surrogate antigen derived from ovalbumin and the Mtb specific ESAT6 antigen were generated and tested for immunogenicity in vaccinated mice. We found that BCG displaying ovalbumin antigen induces an immune response with a magnitude similar to that induced by BCG genetically expressing the same surrogate antigen. We also found that BCG decorated with Mtb specific antigen ESAT6 successfully induces the expansion of specific T cell responses. This novel technology, therefore, represents a practical and effective alternative to DNA-based gene expression for upgrading the current BCG vaccine.
[Mh] Termos MeSH primário: Vacina BCG/imunologia
[Mh] Termos MeSH secundário: Animais
Antígenos de Bactérias/genética
Antígenos de Bactérias/imunologia
Antígenos de Superfície/genética
Avidina/genética
Avidina/imunologia
Avidina/metabolismo
Vacina BCG/genética
Proteínas de Bactérias/genética
Proteínas de Bactérias/imunologia
Biotina/metabolismo
Linhagem Celular
Membrana Celular/imunologia
Membrana Celular/metabolismo
Feminino
Antígenos H-2/metabolismo
Macrófagos/imunologia
Macrófagos/microbiologia
Camundongos
Camundongos Endogâmicos C57BL
Mycobacterium bovis/genética
Mycobacterium bovis/imunologia
Mycobacterium bovis/metabolismo
Mycobacterium tuberculosis/genética
Mycobacterium tuberculosis/imunologia
Ovalbumina/genética
Ovalbumina/imunologia
Fagocitose
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/imunologia
Vacinas Sintéticas/genética
Vacinas Sintéticas/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antigens, Bacterial); 0 (Antigens, Surface); 0 (BCG Vaccine); 0 (Bacterial Proteins); 0 (ESAT-6 protein, Mycobacterium tuberculosis); 0 (H-2 Antigens); 0 (Recombinant Fusion Proteins); 0 (Vaccines, Synthetic); 1405-69-2 (Avidin); 6SO6U10H04 (Biotin); 9006-59-1 (Ovalbumin)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151231
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0145833


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[PMID]:26714929
[Au] Autor:Ghanem E; Al-Balushi M
[Ad] Endereço:Department of Biology, Faculty of Natural and Applied Sciences, Notre Dame University, 72, Zouk Mosbeh, Keserwan district, Lebanon. eghanem@ndu.edu.lb.
[Ti] Título:Adopting the rapamycin trapping assay to track the trafficking of murine MHC class I alleles, H-2K(b).
[So] Source:BMC Cell Biol;16:30, 2015 Dec 29.
[Is] ISSN:1471-2121
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: In mammalian cells, the quality control (QC) of properly folded proteins is monitored in the early secretory pathway, particularly in the endoplasmic reticulum (ER). Several proteins, including our protein of interest, major histocompatibility complex class I (MHC class I), can bypass the first line of ER-QC and reside in post-ER compartments in an unfolded form. Such forms entail both monomeric and dimeric structures that are devoid of peptides and thus cannot fulfill the immunological function of antigen presentation at the cell surface. MHC class I structures become mature and properly folded once loaded with the appropriate peptides in the framework of the peptide loading complex (PLC). Despite the flood of information on the diverse trafficking behavior of different MHC class I alleles, there is still controversy on the actual trajectory followed by improperly folded murine MHC class I alleles, namely H-2Kb. In this study, we employ an in vitro rapamycin trapping assay, live cell imaging, and a biochemical COPII budding approach to further investigate the trafficking of H-2Kb beyond the level of the ER. RESULTS: We confirm the egress of H-2Kb in an unfolded form to a post-ER compartment from where they can cycle back to the ER. Deciphering the exact identity of the post-ER compartment by laser scanning microscopy did not only point to the existence of the ERGIC and cis-Golgi compartments as residency areas for unfolded proteins, but also to the involvement of an addional compartment, that lies in close proximity and possesses high resemblance to the aforementioned compartments. Interestingly, we were capable of showing using the same rapamycin trapping assay that H-2Kb can undergo a potential maturation event during their cycling; this is attained upon addition of peptides and trapping of accumulated post-ER molecules at the cell surface. CONCLUSIONS: Our findings deepen the understanding of H-2Kb trafficking outside the ER and pave the way to decipher the role and the trafficking of certain PLC chaperones, such as tapasin, throughout H-2K(b) post-ER QC. Finally, we demonstrate the plausible usage of the rapamycin assay to assess the trafficking of defected proteins especially in diseases and under therapeutic studies.
[Mh] Termos MeSH primário: Bioquímica/métodos
Antígenos H-2/metabolismo
Sirolimo/farmacologia
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Retículo Endoplasmático/metabolismo
Complexo de Golgi/metabolismo
Antígenos H-2/química
Antígenos H-2/genética
Camundongos
Dobramento de Proteína
Transporte Proteico/efeitos dos fármacos
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (H-2 Antigens); 0 (H-2Kb protein, mouse); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151231
[St] Status:MEDLINE
[do] DOI:10.1186/s12860-015-0077-1



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