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[PMID]:28842469
[Au] Autor:Fischer JC; Otten V; Kober M; Drees C; Rosenbaum M; Schmickl M; Heidegger S; Beyaert R; van Loo G; Li XC; Peschel C; Schmidt-Supprian M; Haas T; Spoerl S; Poeck H
[Ad] Endereço:Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar, Technische Universität, 81675 Munich, Germany.
[Ti] Título:A20 Restrains Thymic Regulatory T Cell Development.
[So] Source:J Immunol;199(7):2356-2365, 2017 Oct 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Maintaining immune tolerance requires the production of Foxp3-expressing regulatory T (T ) cells in the thymus. Activation of NF-κB transcription factors is critically required for T cell development, partly via initiating Foxp3 expression. NF-κB activation is controlled by a negative feedback regulation through the ubiquitin editing enzyme A20, which reduces proinflammatory signaling in myeloid cells and B cells. In naive CD4 T cells, A20 prevents kinase RIPK3-dependent necroptosis. Using mice deficient for A20 in T lineage cells, we show that thymic and peripheral T cell compartments are quantitatively enlarged because of a cell-intrinsic developmental advantage of A20-deficient thymic T differentiation. A20-deficient thymic T cells exhibit reduced dependence on IL-2 but unchanged rates of proliferation and apoptosis. Activation of the NF-κB transcription factor RelA was enhanced, whereas nuclear translocation of c-Rel was decreased in A20-deficient thymic T cells. Furthermore, we found that the increase in T cells in T cell-specific A20-deficient mice was already observed in CD4 single-positive CD25 GITR Foxp3 thymic T cell progenitors. T cell precursors expressed high levels of the tumor necrosis factor receptor superfamily molecule GITR, whose stimulation is closely linked to thymic T cell development. A20-deficient T cells efficiently suppressed effector T cell-mediated graft-versus-host disease after allogeneic hematopoietic stem cell transplantation, suggesting normal suppressive function. Holding thymic production of natural T cells in check, A20 thus integrates T cell activity and increased effector T cell survival into an efficient CD4 T cell response.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Linfócitos T Reguladores/fisiologia
Timo/citologia
Timo/fisiologia
Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética
Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Diferenciação Celular
Citometria de Fluxo
Fatores de Transcrição Forkhead/genética
Fatores de Transcrição Forkhead/metabolismo
Regulação da Expressão Gênica
Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética
Doença Enxerto-Hospedeiro/prevenção & controle
Interleucina-2/imunologia
Ativação Linfocitária
Camundongos
NF-kappa B/metabolismo
Proteínas Proto-Oncogênicas c-rel/genética
Transdução de Sinais
Transplante de Células-Tronco
Timo/imunologia
Fator de Transcrição RelA/genética
Proteína 3 Induzida por Fator de Necrose Tumoral alfa/deficiência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Forkhead Transcription Factors); 0 (Foxp3 protein, mouse); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (Interleukin-2); 0 (NF-kappa B); 0 (Proto-Oncogene Proteins c-rel); 0 (Rela protein, mouse); 0 (Tnfrsf18 protein, mouse); 0 (Transcription Factor RelA); EC 3.4.19.12 (Tumor Necrosis Factor alpha-Induced Protein 3); EC 3.4.22.- (Tnfaip3 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170827
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1602102


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[PMID]:28771603
[Au] Autor:Arbour KC; Naidoo J; Steele KE; Ni A; Moreira AL; Rekhtman N; Robbins PB; Karakunnel J; Rimner A; Huang J; Riely GJ; Hellmann MD
[Ad] Endereço:Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.
[Ti] Título:Expression of PD-L1 and other immunotherapeutic targets in thymic epithelial tumors.
[So] Source:PLoS One;12(8):e0182665, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The thymus is a critical organ for the development of the adaptive immune system and thymic epithelial tumors (TETs; thymomas and thymic carcinomas) are often associated with auto-immune paraneoplastic conditions. However, the immunobiology of TETs is not well described. An evaluation of the tumor microenvironment, with particular focus on expression of immunotherapeutic targets, may facilitate and prioritize development of immunotherapy strategies for patients with TETs. METHODS: Tumor tissues from 23 patients with WHO Type B2/B3 thymoma (n = 12) and thymic carcinoma (n = 11) were identified and clinical outcomes were annotated. The expression of membranous PD-L1 on tumor cells, CD3+ and CD8+ tumor infiltrating lymphocytes (TILs), co-stimulatory (CD137, GITR, ICOS), and co-inhibitory immune checkpoint molecules (PD-1, CTLA-4, TIM-3) were assessed semi-quantitatively using immunohistochemistry. RESULTS: PD-L1 positivity (≥ 25% of tumor membrane expression) was frequent in TETs (15/23, 65%), more common in thymomas compared to thymic carcinomas (p<0.01), and was associated with longer overall survival (p = 0.02). TIM-3 and GITR were expressed in all TETs, including 18/23 and 12/23 with at least moderate/high expression, respectively. Moderate/high CD137 expression correlated with CD8+ (p = 0.01) and moderate/high GITR expression co-associated with PD-1 (p = 0.043). CONCLUSIONS: TETs are characterized by frequent PD-L1 expression and PD-L1 is associated with improved survival, suggesting PD-L1 signaling may be biologically important in TETs. Robust expression of markers of immune activation and immunotherapeutic target molecules in TETs emphasizes the potential for development of anti-PD-1/PD-L1 therapies.
[Mh] Termos MeSH primário: Antígeno B7-H1/metabolismo
Biomarcadores Tumorais/metabolismo
Neoplasias Epiteliais e Glandulares/imunologia
Timoma/imunologia
Neoplasias do Timo/imunologia
[Mh] Termos MeSH secundário: Antígeno B7-H1/imunologia
Linfócitos T CD8-Positivos/imunologia
Antígeno CTLA-4/metabolismo
Feminino
Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo
Receptor Celular 2 do Vírus da Hepatite A/metabolismo
Seres Humanos
Subpopulações de Linfócitos/imunologia
Linfócitos do Interstício Tumoral/imunologia
Masculino
Análise de Sobrevida
Análise Serial de Tecidos
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (B7-H1 Antigen); 0 (Biomarkers, Tumor); 0 (CD274 protein, human); 0 (CTLA-4 Antigen); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (HAVCR2 protein, human); 0 (Hepatitis A Virus Cellular Receptor 2); 0 (TNFRSF18 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:170804
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182665


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[PMID]:28724578
[Au] Autor:Miyagawa I; Nakayamada S; Nakano K; Yamagata K; Sakata K; Yamaoka K; Tanaka Y
[Ad] Endereço:First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
[Ti] Título:Induction of Regulatory T Cells and Its Regulation with Insulin-like Growth Factor/Insulin-like Growth Factor Binding Protein-4 by Human Mesenchymal Stem Cells.
[So] Source:J Immunol;199(5):1616-1625, 2017 Sep 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4 T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4 T cells and surface molecule expression on CD4 T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4 T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4 FOXP3 Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulin-like growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4 T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs.
[Mh] Termos MeSH primário: Tolerância Imunológica
Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo
Células Mesenquimais Estromais/fisiologia
Somatomedinas/metabolismo
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Anticorpos Neutralizantes/farmacologia
Antígeno CTLA-4/metabolismo
Proliferação Celular
Células Cultivadas
Técnicas de Cocultura
Fatores de Transcrição Forkhead/metabolismo
Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo
Seres Humanos
Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/imunologia
Subunidade alfa de Receptor de Interleucina-2/metabolismo
Receptor IGF Tipo 1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Neutralizing); 0 (CTLA-4 Antigen); 0 (FOXP3 protein, human); 0 (Forkhead Transcription Factors); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (Insulin-Like Growth Factor Binding Protein 4); 0 (Interleukin-2 Receptor alpha Subunit); 0 (Somatomedins); EC 2.7.10.1 (Receptor, IGF Type 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170721
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1600230


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[PMID]:28611044
[Au] Autor:Sukumar S; Wilson DC; Yu Y; Wong J; Naravula S; Ermakov G; Riener R; Bhagwat B; Necheva AS; Grein J; Churakova T; Mangadu R; Georgiev P; Manfra D; Pinheiro EM; Sriram V; Bailey WJ; Herzyk D; McClanahan TK; Willingham A; Beebe AM; Sadekova S
[Ad] Endereço:Merck Research Laboratories, Palo Alto, California. selvasukumar@yahoo.com.
[Ti] Título:Characterization of MK-4166, a Clinical Agonistic Antibody That Targets Human GITR and Inhibits the Generation and Suppressive Effects of T Regulatory Cells.
[So] Source:Cancer Res;77(16):4378-4388, 2017 Aug 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of T -mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL). We also investigated the role of GITR agonism in human antitumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a phase I clinical study. Expression of human GITR was comparable with that of mouse GITR in tumor-infiltrating T despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of T In human TIL cultures, MK-4166 induced phosphorylation of NFκB and increased expression of dual specificity phosphatase 6 ( ), indicating that MK-4166 activated downstream NFκB and Erk signaling pathways. Furthermore, MK-4166 downregulated mRNA in human tumor infiltrating T , suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the T -mediated suppressive tumor microenvironment. .
[Mh] Termos MeSH primário: Anticorpos/farmacologia
Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos/imunologia
Linhagem Celular Tumoral
Feminino
Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas
Seres Humanos
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C3H
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos DBA
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (TNFRSF18 protein, human); 0 (Tnfrsf18 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-1439


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[PMID]:28542810
[Au] Autor:Wang S; Li Y; Zhu F; Lin F; Luo X; Zhao B; Zhang P; Li D; Gao Y; Liang R; Liu L; Tsun A; Yuan X; Wu K; Li B
[Ad] Endereço:Shanghai Key Laboratory of Bio-energy Crops, School of Life Science, Shanghai University, China.
[Ti] Título:DNMT1 cooperates with MBD4 to inhibit the expression of Glucocorticoid-induced TNFR-related protein in human T cells.
[So] Source:FEBS Lett;591(13):1929-1939, 2017 Jul.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glucocorticoid-induced TNFR-related protein (GITR) is constitutively expressed in T regulatory (Treg) cells and regulates their suppressive function. We identified two methylated CpG islands in the Gitr locus. Using a ChIP assay, we demonstrate that both DNMT1 and methyl-CpG-binding domain Protein 4 (MBD4) bind to the Gitr promoter. Moreover, knockdown of DNMT1 decreases the binding activity of MBD4. We observed much higher levels of both DNMT1 and MBD4 in human CD4 CD25 conventional T (Tconv) cells. Moreover, co-overexpression of DNMT1 and MBD4 in Treg cells significantly inhibits GITR expression and impairs their suppressive activity. Our results reveal a novel molecular mechanism by which MBD4 inhibits GITR expression in a DNMT1-dependent manner.
[Mh] Termos MeSH primário: DNA (Citosina-5-)-Metiltransferases/metabolismo
Endodesoxirribonucleases/metabolismo
Regulação da Expressão Gênica
Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética
Linfócitos T Reguladores/metabolismo
[Mh] Termos MeSH secundário: Ilhas de CpG/genética
DNA (Citosina-5-)-Metiltransferase 1
Metilação de DNA
Seres Humanos
Regiões Promotoras Genéticas/genética
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (TNFRSF18 protein, human); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1); EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases); EC 2.1.1.37 (DNMT1 protein, human); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (MBD4 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:170526
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12690


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[PMID]:28446565
[Au] Autor:Belmar NA; Chan SW; Fox MI; Samayoa JA; Stickler MM; Tran NN; Akamatsu Y; Hollenbaugh D; Harding FA; Alvarez HM
[Ad] Endereço:Oncology Biologics Department, AbbVie Biotherapeutics Inc., Redwood City, CA 94063.
[Ti] Título:Murinization and H Chain Isotype Matching of the Anti-GITR Antibody DTA-1 Reduces Immunogenicity-Mediated Anaphylaxis in C57BL/6 Mice.
[So] Source:J Immunol;198(11):4502-4512, 2017 Jun 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recent advances in immuno-oncology have shown that the immune system can be activated to induce long-term, durable antitumor responses. For immuno-oncology drug development, immune activation is often explored using rat Abs in immunocompetent mouse models. Although these models can be used to show efficacy, antidrug immune responses to experimental protein-based therapeutics can arise. Immunogenicity of surrogate Abs may therefore represent an important obstacle to the evaluation of the antitumor efficacy of immunomodulator Abs in syngeneic models. A recent publication has shown that anti-glucocorticoid-induced TNFR family-related protein agonistic Ab DTA-1 (rat or murinized IgG2a) can induce the development of anaphylaxis in C57BL/6 mice upon repeated i.p. dosing because of an anti-idiotypic anti-drug Ab immune response. This study was undertaken to address the impact of the immunogenicity derived from the Fc and variable domains. To this end, chimerized (rat V domains/mouse constant regions) and murinized (95% mouse sequence) DTA-1-based surrogate Abs with a murine IgG2c H chain isotype were created. Chimerization and murinization of DTA-1 did not affect receptor binding and glucocorticoid-induced TNFR family-related protein-induced T cell agonistic properties. Similar in vivo antitumor efficacy and intratumoral CD8 /regulatory T cells were also observed. Finally, treatment of C57BL/6 mice with the chimerized and murinized DTA-1 Abs on a C57BL/6-matched IgG2c isotype resulted in reduced development and severity of anaphylaxis as measured by decline of body temperature, behavioral effects, serum IL-4, IgE, and anti-drug Ab levels. These results suggest that careful murinization and selection of a strain-matched H chain isotype are critical to generate ideal surrogate Abs for testing immuno-oncology mechanisms in vivo.
[Mh] Termos MeSH primário: Anafilaxia/imunologia
Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia
Isotipos de Imunoglobulinas/imunologia
[Mh] Termos MeSH secundário: Animais
Linfócitos T CD8-Positivos/imunologia
Linhagem Celular Tumoral
Interleucina-4/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Ratos
Receptores de IgG/imunologia
Linfócitos T Reguladores/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (IgG2c receptor); 0 (Immunoglobulin Isotypes); 0 (Receptors, IgG); 0 (Tnfrsf18 protein, mouse); 207137-56-2 (Interleukin-4)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601512


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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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[PMID]:28122327
[Au] Autor:Mahne AE; Mauze S; Joyce-Shaikh B; Xia J; Bowman EP; Beebe AM; Cua DJ; Jain R
[Ad] Endereço:Merck Research Laboratories, Palo Alto, California.
[Ti] Título:Dual Roles for Regulatory T-cell Depletion and Costimulatory Signaling in Agonistic GITR Targeting for Tumor Immunotherapy.
[So] Source:Cancer Res;77(5):1108-1118, 2017 Mar 01.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Agonistic monoclonal antibodies (mAb) targeting the T-cell receptor coregulatory molecule GITR exert potent therapeutic activities in preclinical tumor models. Although anti-GITR mAb are thought to act by depleting and destabilizing the intratumoral T regulatory cell (Treg) population, the precise mechanism of action is obscure. Here, we addressed this issue using a Treg fate-mapping approach, which revealed that Treg loss was primarily due to cell depletion, with minimal evidence of Treg conversion to a non-Foxp3-expressing population. Further characterization of persisting Tregs following anti-GITR mAb treatment showed that a highly activated subpopulation of CD44 ICOS intratumoral Tregs were preferentially targeted for elimination, with the remaining Tregs exhibiting a less suppressive phenotype. With these changes in the Treg population, intratumoral CD8 T cells acquired a more functional phenotype characterized by downregulation of the exhaustion markers PD-1 and LAG-3. This reversal of CD8 T-cell exhaustion was dependent on both agonistic GITR signaling and Treg depletion, as neither mechanism by itself could fully rescue the exhaustion phenotype. Tests of anti-human GITR antibody MK-4166 in a humanized mouse model of cancer mimicked many of the effects of anti-mouse GITR mAb in syngeneic tumor models, decreasing both Treg numbers and immune suppressor phenotype while enhancing effector responsiveness. Overall, our results show how anti-GITR mAb shifts Treg populations to enable immune attack on tumors, with clinical implications for molecular markers to modify emerging treatments. .
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Neoplasias do Colo/terapia
Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia
Depleção Linfocítica/métodos
Melanoma/terapia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/imunologia
Linhagem Celular Tumoral
Neoplasias do Colo/imunologia
Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas
Seres Humanos
Imunoterapia/métodos
Melanoma/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Glucocorticoid-Induced TNFR-Related Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170126
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-0797


  9 / 373 MEDLINE  
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[PMID]:28101786
[Au] Autor:Ghezeldasht SA; Sadeghian H; Azarpazhooh MR; Shamsian SAA; Rafatpanah H; Mahmoodi M; Rezaee SA
[Ad] Endereço:Research Center for HIV/AIDS, HTLV and Viral Hepatitis, Iranian Academic Center for Education, Culture & Research (ACECR), Mashhad Branch, Mashhad, Iran.
[Ti] Título:Evaluation of T Regulatory Lymphocytes Transcription Factors in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Patients.
[So] Source:Appl Biochem Biotechnol;182(4):1403-1414, 2017 Aug.
[Is] ISSN:1559-0291
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an aggressive neurological disease. The CD4 CD25 T cell population plays pivotal roles in the maintenance of immunological tolerance and prevention of such autoimmune diseases. In the current study, proviral load (PVL), factor forkhead box p3 (Foxp3), and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) gene expression and regulatory T cells (Tregs) counts of 21 HAM/TSP patients and 16 HTLV-1 healthy carriers (ACs) were measured using real-time PCR, TaqMan method, and flow cytometry. The demographic, history of disease, and severity of myelopathy were assessed by a checklist and the Osame motor disability score (OMDS). The mean OMDS for HAM/TSP was 4.82 ± 2.37 which had no significant correlation with Treg count or the expression of Foxp3, GITR, and PVL. The CD4 CD25 cell counts had no significant differences between HAM/TSP and ACs. Findings revealed a higher PVL in HAM/TSPs (313.36 copies/10 ) compared to ACs (144.93 copies/10 , p = 0.035). The Foxp3 and GITR mRNA levels were lower in HAM/TSP patients (11.78 and 13.80, respectively) than those in healthy carriers (18.44 and 21.00, p = 0.041 and 0.03, respectively). There was a significant correlation between Treg frequency and Foxp3 gene expression (R = 0.67, p = 0.006) and GITR and Foxp3 (R = 0.84, p = 0.042) in HAM/TSP patients. Furthermore, the transcription factors have strong correlations with CD4 CD25 T cell frequencies. These findings suggest that HTLV-1 infection can modify the expression of main functional transcription factors, FOXP3 and GITR, which may lead to immune response deterioration of Tregs and consequently HAM/TSP manifestation.
[Mh] Termos MeSH primário: Fatores de Transcrição Forkhead/metabolismo
Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo
Vírus 1 Linfotrópico T Humano/fisiologia
Paraparesia Espástica Tropical/imunologia
Paraparesia Espástica Tropical/metabolismo
Linfócitos T Reguladores/metabolismo
[Mh] Termos MeSH secundário: Adulto
Estudos de Casos e Controles
Contagem de Células
Feminino
Fatores de Transcrição Forkhead/genética
Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética
Seres Humanos
Masculino
Meia-Idade
Paraparesia Espástica Tropical/genética
Linfócitos T Reguladores/citologia
Carga Viral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (FOXP3 protein, human); 0 (Forkhead Transcription Factors); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (TNFRSF18 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170120
[St] Status:MEDLINE
[do] DOI:10.1007/s12010-017-2406-7


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[PMID]:27618667
[Au] Autor:Sales-Campos H; de Souza PR; Basso PJ; Nardini V; Silva A; Banquieri F; Alves VB; Chica JE; Nomizo A; Cardoso CR
[Ad] Endereço:Departamento de Análises Clínicas, Toxicológicas e Bromatológicas - Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil.
[Ti] Título:Amelioration of experimental colitis after short-term therapy with glucocorticoid and its relationship to the induction of different regulatory markers.
[So] Source:Immunology;150(1):115-126, 2017 Jan.
[Is] ISSN:1365-2567
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The clinical benefits of short-term therapy with glucocorticoids (GC) in patients with inflammatory bowel disease (IBD) are widely known. However, the effects of this treatment towards the re-establishment of the regulatory network in IBD are not fully explored. We have evaluated the immunological effects of the abbreviated GC therapy in experimental colitis induced by 3% dextran sulphate sodium in C57BL/6 mice. Treatment with GC improved disease outcome, constrained circulating leucocytes and ameliorated intestinal inflammation. The control of the local inflammatory responses involved a reduction in the expression of interferon-γ and interleukin-1ß, associated with augmented mRNA levels of peroxisome proliferator-activated receptors (α and γ) in intestine. Furthermore, there was a reduction of CD4 T cells producing interferon-γ, together with an increased frequency of the putative regulatory population of T cells producing interleukin-10, in spleen. These systemic alterations were accompanied by a decrease in the proliferative potential of splenocytes of mice treated in vivo with GC. Notably, treatment with GC also led to an increase in the frequency of the regulatory markers GITR, CTLA-4, PD-1, CD73 and FoxP3, more prominently in spleen. Taken together, our results pointed to a role of GC in the control of leucocyte responsiveness and re-establishment of a regulatory system, which probably contributed to disease control and the restoration of immune balance. Finally, this is the first time that GC treatment was associated with the modulation of a broad number of regulatory markers in an experimental model of colitis.
[Mh] Termos MeSH primário: Colite/tratamento farmacológico
Glucocorticoides/uso terapêutico
Subpopulações de Linfócitos T/imunologia
Linfócitos T Reguladores/imunologia
[Mh] Termos MeSH secundário: Animais
Antígenos CD4/metabolismo
Células Cultivadas
Protocolos Clínicos
Colite/induzido quimicamente
Sulfato de Dextrana
Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo
Seres Humanos
Imunomodulação
Interferon gama/metabolismo
Interleucina-10/metabolismo
Interleucina-1beta/metabolismo
Masculino
Camundongos
Receptores Ativados por Proliferador de Peroxissomo/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD4 Antigens); 0 (Glucocorticoid-Induced TNFR-Related Protein); 0 (Glucocorticoids); 0 (Interleukin-1beta); 0 (Peroxisome Proliferator-Activated Receptors); 0 (Tnfrsf18 protein, mouse); 130068-27-8 (Interleukin-10); 82115-62-6 (Interferon-gamma); 9042-14-2 (Dextran Sulfate)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160913
[St] Status:MEDLINE
[do] DOI:10.1111/imm.12672



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